- freely available
Brain Sci. 2013, 3(1), 239-261; doi:10.3390/brainsci3010239
Published: 7 March 2013
Abstract: Stem cell-based therapies for stroke have expanded substantially over the last decade. The diversity of embryonic and adult tissue sources provides researchers with the ability to harvest an ample supply of stem cells. However, the optimal conditions of stem cell use are still being determined. Along this line of the need for optimization studies, we discuss studies that demonstrate effective dose, timing, and route of stem cells. We recognize that stem cell derivations also provide uniquely individual difficulties and limitations in their therapeutic applications. This review will outline the current knowledge, including benefits and challenges, of the many current sources of stem cells for stroke therapy.
1. An Overview of Tailoring Stem Cell Therapy for Stroke
Different tissue-derived adult stem cells can be employed as donor cells for transplantation therapy in stroke. An important factor in considering stem cells for therapy is their use as autologous versus allogeneic cells. Autologous stem cell treatment involves procuring the cells from the same individual in which the cells will be used, compared to receiving cells from an unrelated donor in the case of allogeneic stem cell transplantation. A potential limitation of allogeneic stem cell grafts includes their predisposition for eliciting an immunogenic complication from the host, such as graft rejection. On the other hand, autologous stem cell transplantation also has limitations. The current research for favorable outcomes suggests an optimal combination of intravenous administration, 48 h post-stroke, and a therapeutic dose of 1 million cells [1,2,3]. This short period of opportunity poses a challenge in generating an ample supply of enough stem cells from freshly harvested autologous tissue sources. Ease of harvesting also has a great influence over the practicality of therapeutic potential, regardless of autologous or allogenic cells. Some of the techniques require highly invasive procedures or present ethical problems with acquiring the stem cells, such as neural stem cells and embryonic stem cells, respectively.
Immunological reactions, such as graft vs. host, along with complications secondary to adjunctive immunosuppression, impart another barrier of stem cell treatment for stroke. The immunosuppressant cyclosporine A promotes endogenous neural stem cell activity and migration, thus aiding in the recovery of cortical injury following a stroke . Stroke research in immunocompromised animals has documented elevated endogenous neurogenesis via a CD4+ T cell, but not a CD25+ T cell-dependent mechanism . Despite the possibility for stem cells to produce an immunogenic response, it is evident that the more naive or less lineage-specific a cell, the less likely it is to invoke an immune response. For example, due to immunological immaturity, umbilical cord blood transplantation is less likely to require immunosuppression. Subsequently, human leukocyte antigen (HLA) matching is less strict preceding transplantation while cell viability remains high compared to the requirements for bone marrow transplants . Mesenchymal stem cells, which can be harvested from a variety of mesenchymal tissues, have different characteristics in an immune response depending on its origin. For example, chorionic plate-derived mesenchymal stem cells show higher expression of HLA-G, which is a contributing factor to induce a stronger immunosuppression  and a prognostic indicator of graft tolerance , in comparison with bone marrow-derived and adipose tissue-derived mesenchymal stem cells . Placenta-derived mesenchymal stem cells show less inhibition of CD4+ T cell stimulation than bone marrow-derived stem cells .
In this review, we will provide insights on the different tissues used to harvest stem cells, along with both their limitations and advantages, for stroke neuroprotection. An overview of stem cells currently being investigated for neurorestoration has previously been published .
2. Embryonic Stem Cells
Embryonic stem (ES) cells have arguably been used as the yardstick of “stemness” properties, providing access to an indefinite supply of stem cells that populate all three germ layers. Two major caveats that hinder the use of ES cells for transplantation therapy relate to the ethical concerns and risk of tumorgenicity [12,13]. In this section, ES cell-derived cell transplantation is discussed and not direct transplantation of ES cells per se. ES cell-derived neural progenitor cells transplanted in stroke mice models have been shown to contribute to the repair of neuronal damage . Transplantation of endothelial cells and mural cells derived from ES cells have the potential to contribute to therapeutic vascular regeneration and subsequent reduction of infarct area after stroke in mice . With specific manipulations, human ES cells can be differentiated into neural stem cells called SD56, which do not form tumors after transplantation . Additionally, gene manipulation of ES cell-derived cells have been reported to facilitate therapeutic effects by overexpressing neuroprotective factors such as Bcl-2, adenosine, and myocyte enhancer factor 2C [17,18,19]. Such transplantation of ES cell-derived cells also results in functional recovery in animal ischemic models [17,18,20,21,22].
3. Adult Stem Cells
A primary challenge with sources for adult stem cells is the purification of a homogeneous stem cell population, since the adult tissue source contains non-stem cells that have already been committed to specific lineages. The nature of stroke and stem cell mode of action are both diverse. Because of this, there is special consideration given to the use of specific stem cell derivatives to treat specific stroke conditions.
3.1. Bone Marrow-Derived Stem Cells
Diverse populations of cells constitute the bone marrow. These cells are purified to harvest an isolated cell type or used as a mixture. Research emerging within the last decade suggests the feasibility of bone marrow-derived stem cells for stroke therapy. Data demonstrate that, upon injury, bone marrow-derived stem cells can mobilize from the bone marrow (BM) and migrate into the peripheral blood. Once in systemic vasculature, they then can enter the central nervous system to influence neuronal injury . Cell constituents of bone marrow include: hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), and very small embryonic-like stem cells (VSELs) . We will outline the therapeutic potential of these bone marrow-derived stem cell lines in the following sections.
3.1.1. Hematopoietic Stem Cells
Hematopoietic stem cells (HSCs), of the phenotype CD34+  with additional surface markers CD150+, CD244−, and CD48− , can differentiate into all blood cells. In response to a cerebrovascular incident such as stroke, the CNS can produce cytokines that induce HSC mobilization [27,28,29,30]. Neurotransmitters, most notably catecholamines, can induce HSC mobilization through a nerve ending paracrine signal directly into bone marrow or through sympathetic release into blood circulation . Current treatment protocols, such as granulocyte-colony stimulating factor (G-CSF), apply this cytokine-mediated recruitment [29,30]. Human clinical data of acute stroke shows an abundant mobilization of peripheral blood immature hematopoietic CD34+ cells, colony-forming cells, and long-term culture-initiating cells . The magnitude of mobilization appears to correlate with the recovery of function . More so, the infusion of autologous bone marrow mononuclear cells containing HSCs, in addition to cell types including mesenchymal stromal cells and lymphocytes, has been reported in human stroke patients [34,35,36,37]. Those studies, which include the acute, subacute, and chronic phases of stroke, show no adverse effects of transplantation. Transplantation of bone marrow mononuclear cells increases plasma β-nerve growth factor . The amount of CD34+ cells in mononuclear cells transplanted shows a trend of positive correlation with rate of functional recovery .
3.1.2. Mesenchymal Stromal Cells
Mesenchymal stromal cells, of the phenotype SH2+, SH3+, SH4+, CD29+, CD44+, CD14−, CD34−, and CD45−, are found in nearly all tissues of the body and can differentiated into mesenchymal tissues such as osteogenic, chondrogenic, and adipogenic cells. In this section, we will first discuss the use of mesenchymal stromal cells derived from bone marrow (BM) for the treatment of stroke, but also describe the use of the non-bone-marrow-derived mesenchymal stromal cells.
The use of BM-derived mesenchymal stromal cells prompts functional recovery of neurological deficits succeeding cerebral ischemia in stroke models [39,40,41]. Mesenchymal stromal cell transplantation benefits are imparted by the introduction of neurotrophic factors that activate endogenous brain tissue. These factors include: hepatocyte growth factor (HGF) [39,42], vascular endothelial growth factor (VEGF) , nerve growth factor (NGF) , brain-derived neurotrophic factor (BDNF) , basic fibroblast growth factor (bFGF, FGF-2) , and insulin growth factor-1 (IGF-1) . In addition to secreting such factors, the presence of MSCs may promote endogenous induction and migration of primary stem cells from their usual locations (SVZ and SGZ) to the location of injury, while also reducing apoptosis in the penumbral zone of the lesion [43,44]. Whether or not mesenchymal stromal cells differentiate into functional neurons, there is an indication that these cells promote neurogenesis after a stroke injury, but do not have long-term survival after transplantation . Much like neural stem cells, the benefits may also arise from the production of neurotrophic factors such as BDNF, β-NGF , and the modulation of vasculature observed equally from four different sources: bone marrow, adipose tissue, skeletal muscle, and myocardium . A clinical trial of intravenous infusion of autologous BM-derived mesenchymal stromal cells in ischemic stroke patients shows significant functional improvement in infused patients without adverse effects in comparison with non-infused patients . Five-year follow-ups of mesenchymal stromal cell-infused patients also show a higher survival rate and functional improvement than non-infused patients .
Mesenchymal stromal cells are the most commonly studied stem cell derived from extraembryonic tissue. Unlike neural stem cells from the ectoderm-derived tissue of the nervous system, mesoderm-derived mesenchymal stromal cells can be isolated from nearly all mesenchymal tissues of the body, including bone marrow, placenta, teeth, and adipose tissue. The abundance of potential harvesting sites makes mesenchymal stromal cells a favorable line for autologous transplantation. However, potential discrepancies have prompted the International Society for Cellular Therapy (ISCT) to define minimal criteria for definition of a stem cell as a mesenchymal stromal cell. Plastic adherence, cluster of differentiation (CD) expression, and differentiation ability are some of the characteristics considered .
Although mesenchymal stromal cells are harvested from mesenchyme-derived tissues, evidence reports that mesenchymal stromal cells from different locations may impart specific roles as a function of the various ways they are extracted, isolated, and proliferated [51,52,53,54,55]. To this extent, one site of tissue-derived mesenchymal stromal cells may be better qualified for a specific therapy than cells derived from another. Differences also exist between mesenchyme-derived stromal cells and other stem cells. For example, research in bone marrow-derived stem cells in horses established that these cells reach senesce at earlier passages than adipose and umbilical cord-derived cells in mesenchymal tissue .
Much like neural stem cells, described later in this paper, the risk of mesenchymal stem cells developing into tumors must be considered. The literature notes a sarcoma developed in the lungs after mesenchymal stem cells were transplanted in mice . Also, secretions from mesenchymal stem cells affect tumors. The combination of interleukin-6 (IL-6) and vascular endothelial growth factor A (VEGF) secreted from mesenchymal stem cells increases the ability of breast cancer cell lines to migrate . Breast cancer cells stimulate de novo secretion of the chemokine CCL5 from mesenchymal stem cells, which then acts in a paracrine fashion on the cancer cells to enhance their motility, invasion, and metastasis . Consequently, mesenchymal stem cells of specific derivations may have a greater propensity for tumorigenesis and encouraging metastasis. This may not be the case for all mesenchyme-derived stromal cells, however. Research suggests umbilical cord mesenchymal stem cells do not appear to develop into tumor progenitor cells in the presence of tumor cells, unlike bone marrow-derived mesenchymal stromal cells .
3.1.3. Endothelial Progenitor Cells
Stroke is multifactorial in etiology. One such factor involves the disruption in vascular integrity, causing vessel vulnerability that predisposes the region to a stroke-like event. The endothelium modulates the permeability of the blood-brain-barrier and thus stroke recovery. Endothelial progenitor cells (EPCs) are precursors for the mature endothelium that lines the vascular system, a role that has long been established . EPCs are defined as cells that express HSC markers such as CD34 or CD133 and the marker protein vascular endothelial growth factor receptor 2 (VEGRF2) . In an early study, transplanted EPCs were found in newly vascularized endothelium of surgically induced ischemic hind limb injury in rabbits . More recent research indicates that circulating BM-derived EPCs are signaled to sites for neovascularization, where they will differentiate into endothelial cells [64,65]. A correlational study in human ischemic stroke patients indicates that the level of circulating EPCs relates to improvement on the National Institute of Health Stroke Scale . An animal model of stroke shows that tail vein injection of EPCs reduces infarct induction through middle cerebral artery occlusion (MCAO) in diabetic mice . Also, intravenous infusion of autologous EPCs after MCAO in rabbits shows functional improvement, decreasing the number of apoptotic cells, increasing microvessel density in the ischemic boundary area, and diminishing the infarct area . The research of EPCs and stroke-related vascularization is still sparse, but the evidence is surmounting that they could play a constitutional role in the prevention of stroke and the treatment after an injury.
3.1.4. Very Small Embryonic-Like Stem Cells
Much like the hematopoietic stem cells discussed above, very small embryonic-like stem cells (VSELs), which have the phenotype Sca-1+, lin−, CD45- and also have pluripotent stem cell markers such as SSEA-1, Oct-4, Nanog, and Rex-1 , are mobilized from adult tissues into the peripheral blood following a stroke event [70,71,72]. The current hypothesis is that VSELs are epiblast-derived pluripotent stem cells that are deposited early during embryonic development [73,74], serving as a reserve within the tissue that can be utilized for rejuvenation. The brain is one such location that includes a large number of cells displaying the VSEL phenotype [75,76]. The ability for VSELs to differentiate into neurons, oligodendrocytes, and microglia to regenerate damaged CNS makes them an excellent candidate for stroke therapy . However, limitations currently exist when considering the use of VSELs. One such obstacle is the low yield of VSELs from harvesting. This restraint requires the necessity for proliferation prior to transplantation . Another restriction is the decrease in number of VSELs with age, thereby exacerbating the difficulty in harvesting an adequate number of cells in older individuals .
3.2. Neural Stem Cells
In terms of stroke injury, the use of neural stem cells (NSCs) seems like an apparent solution. Endogenous stem cells are located in the subgranular zone (SGZ) of the dentate gyrus, the subventricular zone (SVZ), and the subependymal zone (SEZ) of the spinal cord. As one may anticipate, the cellular activity is upregulated in these zones following a stroke-like injury; yet, this action does not provide cell replacement or full functional repair, despite NSCs being found at the site of ischemic lesions from day 1 after stroke in human patients .
NSCs in the SVZ migrate into ischemic lesions after stroke. NSCs from the SVZ are redirected from their normal route through the rostral stream into a redefined direction to reach ischemic regions along blood vessels as a scaffold for migration [79,80,81]. Chemokine signals such as stromal-derived factor-1 (SDF-1), vascular endothelial growth factor (VEGF), and angiopoietin are released from ischemic tissue, influencing the course of the SVZ NSCs toward a path along blood vessels to reach the infarcted area [82,83,84,85]. In ex vivo cultures of rat brain cells, microglia from ischemic brain, but not from intact brain, promotes differentiation of SVZ NSCs into neurons, suggesting that microglia might have a role on differentiation of NPCs . However, in vivo studies demonstrated that a very low number—or even possibly none of the newborn cells—develop into mature neurons [87,88,89].
While endogenous NPCs migrate and differentiate into mature neurons, this may not be sufficient for self-repair of ischemic brain. Current literature explores the idea of exogenous stem cell transplantation eliciting endogenous stem cell production at the site of injury [90,91]. The intravenous infusion of neural progenitor cells produces increased dendritic length and an increased number of branch points in host neurons . Transplanted NSCs have therapeutic effects without differentiating into mature neurons , although there is a report that transplanted ES cell-derived NSCs in the ischemic rat brain differentiated into neurons, into oligodendlocytes in stroke regions undergoing remyelination, and into astrocytes extending processes toward stroke-damaged vasculatures . Even with the beneficial effects of NSC transplantation on endogenous stem cell proliferation, it still has limitations. A primary limitation is the acquisition of these cells. An autologous treatment would require invasive surgery prior to therapy and allogenic grafts would likely require a fetal source or derivation from an alternative cell type. Another possibility would be harvesting the cells during other surgical procedures , but this may not be very advantageous. One of the foremost concerning consequences is the potential of stem cells to be tumorigenic. Somewhat contradictorily of immunogenicity, the less differentiated the cell, the greater the potential for the cell line to generate aberrant proliferation. Thus, adult stem cells, due to progressive differentiation, are less likely than embryonic stem cells to encourage tumorigenesis. Additionally, when utilizing stem cells, it is essential to ensure that the transplantation consists of a purified cell population [96,97]. A prior case identified this necessity when a child with ataxia telangiectasia was transplanted with a heterogeneous mixture of fetally derived neural stem cells and was diagnosed with a glioneuroal neoplasm four years later .
A possible explanation for the potential reduction in tumorigenesis of adult-derived stem cells is due to their reduced capacity to proliferate. A likely benefit for avoiding neoplastic events is, unfortunately, a problem when attempting to achieve a sufficient number of stem cells for transplantation. To navigate these limitations, researchers have developed methods such as long-term culturing, immortalization, insertion of oncogenes, or even deriving neural stem cells from other tissues or from pluripotent stem cells. However, each of the aforementioned methods has inherent limitations. Long-term culturing, for instance, bears the risk of spontaneous conversion to a non-neural cell type, such as a tumor precursor cell . In spite of the teratocarcinoma-derived hNT neuron cell lines advancing into a phase II clinical trial in stroke patients , no significant improvements were observed . Oncogene insertion may still have a favorable future. ReNeuron LTD, a stem cell therapeutics company based in England, is using a c-Myc regulator gene and mutated estrogen receptor transgene to generate an immortalized neural cell line . This protocol is currently undergoing clinical trials for stroke in the United Kingdom .
3.3. Extraembryonic Stem Cells
Tissues rich in extraembryonic stem cells include: umbilical cord, placenta, amnion, and Wharton’s jelly. As discussed above, mesenchymal stromal cells are the most popular cell line for study, but amnioitic epithelial cells, amnion-derived stem cells, placental-derived stem cells, and umbilical cord matrix stem cells can also be found in extraembryonic tissue . Extraembryonic stem cells, much like NSCs and mesenchymal stromal cells, pertain to different germinal layers. The ectoderm gives rise to the amniotic epithelium, while the amnion-derived mesenchymal stromal cells are found in the mesodermal layer . Therefore, amnion-derived stem cells appear to contain a higher capacity for mesodermal cell lineages than the ectoderm . Amnion mesenchymal stromal cells also exhibit less endothelial capabilities, further demonstrating potential embryonic specificity .
Current studies with extraembryonic stem cells investigate transplanting animal models of stroke with placental-derived mesenchymal stromal cells. In congruence with the proposed mechanism of action, these cells do not appear to solely replace damaged cells. Rather, they appear to furnish the microenvironment in a way that promotes endogenous neurogenesis [108,109,110]. Research with umbilical cord lining mesenchymal stromal cells in rat stroke models demonstrates functional recovery, increased vascular density, increased expression of vascular endothelial growth factor, and basic fibroblast growth factor . Mesenchymal stromal cells derived from the umbilical cord lining also provide an immunosuppressive effect on the immune cascade and appear to have greater immunological immaturity than aged bone marrow mesenchymal stromal cells . Additionally, Wharton’s jelly-derived mesenchymal stromal cells differentiate into glial, neuronal, doublecortin+, CXCR4+, and vascular endothelial cells to enhance neuroplasticity in the ischemic brain  and have an immunosuppressive function by secreting leukemia inhibitory factor (LIF) .
The popularity of umbilical cord banking has been increasingly steadily. Given their possibility for both allogenic and autologous use, these stem cells could have broad therapeutic potential. Umbilical cord blood routinely refers to the mononuclear fraction, which includes hematopoietic progenitors, lymphocytes, monocytes, and mecenchymal stromal cells. Even with its heterogeneity, these cells are considered immunologically immature. Thus, these cells have been reported to modulate the immune response and reduce proinflammatory cytokine levels . In terms of transplantation of umbilical cord blood in animal stroke models, there have been auspicious results. Transplantation of umbilical cord blood-derived stem cells in animal models of stroke demonstrates functional recovery, reducing infarct size, and higher expression of neuroprotective factors, such as BDNF and VEGF [1,2,116,117].
3.4. Other Sources of Adult Stem Cells
3.4.1. Adipose Tissue
Adipose tissue includes adipose-derived stem cells, which are a plastic-adherent cell population and have a more than 90% identical immunophenotye compared to bone marrow-derived mesenchymal stromal cells . Studies with adipose-derived stem cells exhibited reduced infarct size, improved neurological function, reduced level of cerebral inflammation, and chronic degeneration in an intracerebral hemorrhage model [119,120]. Adipose-derived stem cells can differentiate into neural, glial, and vascular endothelial cells, and also show higher proliferative activity with greater production of VEGF and hepatocyte growth factor in comparison with bone marrow-derived stromal cells . Treatment with adipose-derived stem cells in an ischemic stroke model of mice shows remarkable attenuation of ischemic damage .
In spite of the potential benefits for stroke injury as previously noted, there are still side effects associated with adipose-derived stem cells. Extensive passaging of adipose-derived stem cells might cause spontaneous mutations within the cell line that may promote a cancerous state . However, this statement has since been retracted due to the inability to replicate the data . Revisions to these studies have now demonstrated that adipose-derived stem cells can promote preexisting cancerous cells to produce tumors, but do not result in tumors alone . A careful analysis of risk-to-benefit ratio must be observed in order to advance a safe and effective cell therapy for stroke.
3.4.2. Menstrual Blood
With the endometrial lining in the uterus cycling monthly, it has been a location of interest for researchers. Two separate groups have isolated stem cells in this region, although it is unsure if they are the identical cell line due to differences in culturing protocols [125,126]. Menstrual blood-derived stem cells exhibit multipotency. Menstrual blood-derived stem cells secrete trophic factors such as VEGF, BDNF, and NT-3 in response to oxygen glucose deprivation (OGD), an in vitro model of stroke. Co-culture of rat primary neurons with menstrual blood-derived stem cells, or its conditioned medium exposed to OGD, improved cell survival rate after OGD . Both intracerebral and intravenous transplantation of menstrual blood-derived cells into stroke model rats improved host cell survival and behavioral functions . These cells have also been implemented for in vivo surgical MCAO rat studies without immunosuppression [127,128,129].
Mammary tissue includes stem cells. Stem cells and differentiated cells from the lactating epithelium enter breastmilk either through cell migration and turnover and/or as a consequence of the mechanical shear forces of breastfeeding [130,131]. Breastmilk stem cells show embryonic stem cell-like morphology and phenotype, and can be differentiated into cell lineages from all three germ layers in vitro . The presence of stem cells in the breastmilk may provide a great advantage for harvesting these cells while avoiding any invasive procedures . Historically, the benefits of breast milk have been considered nutritive and immunologic, but emerging research is attempting to elucidate the potential effects of vertical transmission of stem cells from mother to offspring . Accompanying the ease of harvesting, breastmilk stem cells also present the potential for autologous transplantation.
3.4.4. Dental Tissue
Dental tissue could prove to be a useful resource in harvesting stem cells in the future. Dental tissue-derived stem cells such as post-natal dental pulp stem cells (DPSCs) , stem cells from exfoliated deciduous teeth (SHED) , periodontal ligament stem cells (PDLSCs) , stem cells from apical papilla (SCAP) [135,136], and dental follicle precursor cells (DFPCs) , which exhibit mesenchymal stromal cells-like capabilities, have been identified (for review, see ).
Dental tissue-derived stem cells can differentiate into a variety of cell types including neural cells, adipocytes, and odontoblasts . Transplantation into intact mouse brain showed cell survival along with expression of neuronal markers . A rodent model of cerebral ischemia shows improved sensorimotor function after receiving transplantation of dental tissue-derived stem cells [140,141]. Transplanted DPSCs differentiate into astrocytes in preference to neurons, suggesting secretion of trophic factors for therapeutic effects . Neurogenicity of dental tissue-derived stem cells is more potent than that of bone marrow-derived stem cells , most likely due to their neural crest origin .
3.4.5. Induced Pluripotent Stem Cells
Once thought to be unidirectional, recent experiments suggest stem cells can be manipulated into their former multipotency. It was originally considered that stem cells progress through maturation to become terminally differentiated. However, the literature indicates that through the transfection of specific transcription factors, embryonic-like stem cells can be regenerated from fibroblasts through retrograde manipulation . This transfection technique has also been applied to umbilical cord, placental mesenchymal stromal cells, neural stem cells, and adipose-derived precursor cells to increase their potency [144,145].
A major benefit of retrograde conversion is the proliferation capacity of precursor cells. Some studies demonstrated beneficial effects of transplantation of induced pluripotent stem cells (iPSCs) in an animal model of stroke, including effects such as: improving sensorimotor functions [146,147], reducing infarct size, reducing pro-inflammatory cytokines, and increasing anti-inflammatory cytokines . However, the use of iPSCs appears to have some ramifications. As with many stem cells, both immunogenicity and tumorigenesis are of concern. The transfection technique used to generate precursor cells utilizes transcription factors of known oncogencity. iPSCs, even when autologous, have also provoked an immune response leading to rejection . In fact, a higher rate of tumorigenesis after transplantation of undifferentiated iPSCs is reported [149,150]. However, pre-differentiated neuroepithelial-like stem cells derived from human fibroblast derived-iPSCs enhances recovery after stroke without forming tumors by four months post-transplantation .
In terms of translational research, although iPSCs have the potential for autologous cell therapy, the technology will need to be significantly improved before this becomes a viable option to treat the acute phase of stroke, specifically the demonstration of feasibility that a well-defined population of IPSCs are banked prior to injury due to the duration required to make enough stem cells for a therapeutic dose. Moreover, any genetic manipulation to IPSCs needs to be regulated, particularly in the post-transplantation period, in order to avoid any potential of tumorgenic or ectopic tissue formation.
4. New Stem Cell Approaches: Co-Transplantation, Combination Therapy, and Others
As evident by the literature thus far, individual stem cells confer discrete therapeutic potential. Thus there is the potential for treatment with multiple stem cell lines, simultaneously. There is evidence of co-transplantation providing synergistic effects on stem cell survival. One such study demonstrated increased neural stem cell survival when neural stem cell delivery was combined with adipose-derived stem cells . An additional study reports that co-transplantation of bone marrow-derived stromal cells with embryonic stem cells decreased the propensity for tumorigenesis . With similar regard, accompanying neural stem cells with epithelial cells increased survival and differentiation .
Combination therapy, similar to co-transplantation of two cell lines, can incorporate a non-stem-cell substrate to increase the efficacy of transplantation. Examples include combining bone marrow-derived stromal cells with trophic factors to enhance survival and potentiation  or providing a scaffold for stem cell adherence . The techniques of co-transplantation and combination therapy are still novel, but the ability to enhance stem cell survival while decreasing adverse events is emerging with current research.
Many of the persisting variables in stem cell techniques have recently been reviewed by us . Factors including optimal dose, route of administration, and sex of donor/recipient are all likely to be contingent upon the cell type being investigated. We have investigated many of these factors with umbilical cord blood for conditions such as amyotrophic lateral sclerosis, Alzheimer’s disease, and Sanfilippo syndrome ; however, this information has yet to be resolved in regards to stroke. The Stem Cell Therapies as an Emerging Paradigm in Stroke (STEPS) program was designed for the purpose of study interpretation in an attempt to standardize procedures [158,159,160,161].
As we reviewed here, there is currently a vast number of sources available for stem cell harvesting, and as the evidence is further substantiated, they may each impart their own benefits and have their own native limitations. Many logistical considerations must be made for the use of stem cells for therapeutic stroke treatment. Such factors include mode of action, immunogenicity, tumorigenicity, harvesting, proliferation capacity, and overall feasibility of use. These variables must be addressed before translational studies can proceed. However, despite the limitations identified and the considerations still needing concrete exploration, limited clinical trials of stem cell therapy for stroke patients are already underway. Parallel laboratory investigations are necessary to further optimize the safety and efficacy of stem cells for clinical applications.
Conflict of Interest
Cesario V. Borlongan holds patents in stem cell technologies for the treatment of neurodegenerative disorders.
- Willing, A.E.; Lixian, J.; Milliken, M.; Poulos, S.; Zigova, T.; Song, S.; Hart, C.; Sanchez-Ramos, J.; Sanberg, P.R. Intravenous versus intrastriatal cord blood administration in a rodent model of stroke. J. Neurosci. Res. 2003, 73, 296–307, doi:10.1002/jnr.10659.
- Vendrame, M.; Cassady, J.; Newcomb, J.; Butler, T.; Pennypacker, K.R.; Zigova, T.; Sanberg, C.D.; Sanberg, P.R.; Willing, A.E. Infusion of human umbilical cord blood cells in a rat model of stroke dose-dependently rescues behavioral deficits and reduces infarct volume. Stroke 2004, 35, 2390–2395, doi:10.1161/01.STR.0000141681.06735.9b.
- Newcomb, J.D.; Ajmo, C.T., Jr.; Sanberg, C.D.; Sanberg, P.R.; Pennypacker, K.R.; Willing, A.E. Timing of cord blood treatment after experimental stroke determines therapeutic efficacy. Cell Transplant. 2006, 15, 213–223, doi:10.3727/000000006783982043.
- Erlandsson, A.; Lin, C.H.; Yu, F.; Morshead, C.M. Immunosuppression promotes endogenous neural stem and progenitor cell migration and tissue regeneration after ischemic injury. Exp. Neurol. 2011, 230, 48–57, doi:10.1016/j.expneurol.2010.05.018.
- Saino, O.; Taguchi, A.; Nakagomi, T.; Nakano-Doi, A.; Kashiwamura, S.; Doe, N.; Nakagomi, N.; Soma, T.; Yoshikawa, H.; Stern, D.M.; et al. Immunodeficiency reduces neural stem/progenitor cell apoptosis and enhances neurogenesis in the cerebral cortex after stroke. J. Neurosci. Res. 2010, 88, 2385–2397.
- Willing, A.E.; Eve, D.J.; Sanberg, P.R. Umbilical cord blood transfusions for prevention of progressive brain injury and induction of neural recovery: An immunological perspective. Regen. Med. 2007, 2, 457–464, doi:10.2217/174607220.127.116.117.
- Hunt, J.S.; Petroff, M.G.; McIntire, R.H.; Ober, C. HLA-G and immune tolerance in pregnancy. FASEB J. 2005, 19, 681–693, doi:10.1096/fj.04-2078rev.
- Menier, C.; Rouas-Freiss, N.; Favier, B.; LeMaoult, J.; Moreau, P.; Carosella, E.D. Recent advances on the non-classical major histocompatibility complex class I HLA-G molecule. Tissue Antigens 2010, 75, 201–206.
- Lee, J.M.; Jung, J.; Lee, H.J.; Jeong, S.J.; Cho, K.J.; Hwang, S.G.; Kim, G.J. Comparison of immunomodulatory effects of placenta mesenchymal stem cells with bone marrow and adipose mesenchymal stem cells. Int. Immunopharmacol. 2012, 13, 219–224, doi:10.1016/j.intimp.2012.03.024.
- Fazekasova, H.; Lechler, R.; Langford, K.; Lombardi, G. Placenta-derived MSCs are partially immunogenic and less immunomodulatory than bone marrow-derived MSCs. J. Tissue Eng. Regen. Med. 2011, 5, 684–694, doi:10.1002/term.362.
- Huang, H.; Chen, L.; Sanberg, P. Cell Therapy from Bench to Bedside Translation in CNS Neurorestoratology Era. Cell Med. 2010, 1, 15–46, doi:10.3727/215517910X516673.
- Asano, T.; Ageyama, N.; Takeuchi, K.; Momoeda, M.; Kitano, Y.; Sasaki, K.; Ueda, Y.; Suzuki, Y.; Kondo, Y.; Torii, R.; et al. Engraftment and tumor formation after allogeneic in utero transplantation of primate embryonic stem cells. Transplantation 2003, 76, 1061–1067, doi:10.1097/01.TP.0000090342.85649.81.
- Riess, P.; Molcanyi, M.; Bentz, K.; Maegele, M.; Simanski, C.; Carlitscheck, C.; Schneider, A.; Hescheler, J.; Bouillon, B.; Schafer, U.; Neugebauer, E. Embryonic stem cell transplantation after experimental traumatic brain injury dramatically improves neurological outcome, but may cause tumors. J. Neurotrauma 2007, 24, 216–225, doi:10.1089/neu.2006.0141.
- Hayashi, J.; Takagi, Y.; Fukuda, H.; Imazato, T.; Nishimura, M.; Fujimoto, M.; Takahashi, J.; Hashimoto, N.; Nozaki, K. Primate embryonic stem cell-derived neuronal progenitors transplanted into ischemic brain. J. Cereb. Blood Flow Metab. 2006, 26, 906–914, doi:10.1038/sj.jcbfm.9600247.
- Oyamada, N.; Itoh, H.; Sone, M.; Yamahara, K.; Miyashita, K.; Park, K.; Taura, D.; Inuzuka, M.; Sonoyama, T.; Tsujimoto, H.; et al. Transplantation of vascular cells derived from human embryonic stem cells contributes to vascular regeneration after stroke in mice. J. Transl. Med. 2008, 6, 54, doi:10.1186/1479-5876-6-54.
- Daadi, M.M.; Maag, A.L.; Steinberg, G.K. Adherent Self-Renewable Human Embryonic Stem Cell-Derived Neural Stem Cell Line: Functional Engraftment in Experimental Stroke Model. PloS One 2008, 3, e1644.
- Wei, L.; Cui, L.; Snider, B.J.; Rivkin, M.; Yu, S.S.; Lee, C.S.; Adams, L.D.; Gottlieb, D.I.; Johnson, E.M.; Yu, S.P.; Choi, D.W. Transplantation of embryonic stem cells overexpressing Bcl-2 promotes functional recovery after transient cerebral ischemia. Neurobiol. Dis. 2005, 19, 183–193, doi:10.1016/j.nbd.2004.12.016.
- Pignataro, G.; Studer, F.E.; Wilz, A.; Simon, R.P.; Boison, D. Neuroprotection in ischemic mouse brain induced by stem cell-derived brain implants. J. Cereb. Blood Flow Metab. 2007, 27, 919–927.
- Li, Z.; McKercher, S.R.; Cui, J.; Nie, Z.G.; Soussou, W.; Roberts, A.J.; Sallmen, T.; Lipton, J.H.; Talantova, M.; Okamoto, S.I.; Lipton, S.A. Myocyte enhancer factor 2C as a neurogenic and antiapoptotic transcription factor in murine embryonic stem cells. J. Neurosci. 2008, 28, 6557–6568, doi:10.1523/JNEUROSCI.0134-08.2008.
- Yanagisawa, D.; Qi, M.; Kim, D.H.; Kitamura, Y.; Inden, M.; Tsuchiya, D.; Takata, K.; Taniguchi, T.; Yoshimoto, K.; Shimoama, S.; et al. Improvement of focal ischemia-induced rat dopaminergic dysfunction by striatal transplantation of mouse embryonic stem cells. Neurosci. Lett. 2006, 407, 74–79, doi:10.1016/j.neulet.2006.08.007.
- Theus, M.H.; Wei, L.; Cui, L.; Francis, K.; Hu, X.Y.; Keogh, C.; Yu, S.P. In vitro hypoxic preconditioning of embryonic stem cells as a strategy of promoting cell survival and functional benefits after transplantation into the ischemic rat brain. Exp. Neurol. 2008, 210, 656–670, doi:10.1016/j.expneurol.2007.12.020.
- Yang, T.; Tsang, K.S.; Poon, W.S.; Ng, H.K. Neurotrophism of Bone Marrow Stromal Cells to Embryonic Stem Cells: Noncontact Induction and Transplantation to a Mouse Ischemic Stroke Model. Cell Transplant. 2009, 18, 391–404, doi:10.3727/096368909788809767.
- Borlongan, C.V.; Glover, L.E.; Tajiri, N.; Kaneko, Y.; Freeman, T.B. The great migration of bone marrow-derived stem cells toward the ischemic brain: Therapeutic implications for stroke and other neurological disorders. Prog. Neurobiol. 2011, 95, 213–228, doi:10.1016/j.pneurobio.2011.08.005.
- Herzog, E.L.; Chai, L.; Krause, D.S. Plasticity of marrow-derived stem cells. Blood 2003, 102, 3483–3493, doi:10.1182/blood-2003-05-1664.
- Krause, D.S.; Ito, T.; Fackler, M.J.; Smith, O.M.; Collector, M.I.; Sharkis, S.J.; May, W.S. Characterization of murine CD34, a marker for hematopoietic progenitor and stem cells. Blood 1994, 84, 691–701.
- Kiel, M.J.; Yilmaz, O.H.; Iwashita, T.; Terhorst, C.; Morrison, S.J. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 2005, 121, 1109–1121, doi:10.1016/j.cell.2005.05.026.
- Lapidot, T.; Dar, A.; Kollet, O. How do stem cells find their way home? Blood 2005, 106, 1901–1910, doi:10.1182/blood-2005-04-1417.
- Lapidot, T.; Kollet, O. The brain-bone-blood triad: Traffic lights for stem-cell homing and mobilization. Hematology Am. Soc. Hematol. Educ. Program 2010, 2010, 1–6, doi:10.1182/asheducation-2010.1.1.
- Nervi, B.; Link, D.C.; DiPersio, J.F. Cytokines and hematopoietic stem cell mobilization. J. Cell. Biochem. 2006, 99, 690–705, doi:10.1002/jcb.21043.
- Papayannopoulou, T.; Scadden, D.T. Stem-cell ecology and stem cells in motion. Blood 2008, 111, 3923–3930, doi:10.1182/blood-2007-08-078147.
- Kalinkovich, A.; Spiegel, A.; Shivtiel, S.; Kollet, O.; Jordaney, N.; Piacibello, W.; Lapidot, T. Blood-forming stem cells are nervous: Direct and indirect regulation of immature human CD34+ cells by the nervous system. Brain Behav. Immun. 2009, 23, 1059–1065, doi:10.1016/j.bbi.2009.03.008.
- Hennemann, B.; Ickenstein, G.; Sauerbruch, S.; Luecke, K.; Haas, S.; Horn, M.; Andreesen, R.; Bogdahn, U.; Winkler, J. Mobilization of CD34+ hematopoietic cells, colony-forming cells and long-term culture-initiating cells into the peripheral blood of patients with an acute cerebral ischemic insult. Cytotherapy 2008, 10, 303–311, doi:10.1080/14653240801949994.
- Dunac, A.; Frelin, C.; Popolo-Blondeau, M.; Chatel, M.; Mahagne, M.H.; Philip, P.J. Neurological and functional recovery in human stroke are associated with peripheral blood CD34+ cell mobilization. J. Neurol. 2007, 254, 327–332, doi:10.1007/s00415-006-0362-1.
- Moniche, F.; Gonzalez, A.; Gonzalez-Marcos, J.R.; Carmona, M.; Pinero, P.; Espigado, I.; Garcia-Solis, D.; Cayuela, A.; Montaner, J.; Boada, C.; et al. Intra-Arterial Bone Marrow Mononuclear Cells in Ischemic Stroke A Pilot Clinical Trial. Stroke 2012, 43, U2242–U2244, doi:10.1161/STROKEAHA.112.659409.
- Savitz, S.I.; Misra, V.; Kasam, M.; Juneja, H.; Cox, C.S.; Alderman, S.; Aisiku, I.; Kar, S.; Gee, A.; Grotta, J.C. Intravenous Autologous Bone Marrow Mononuclear Cells for Ischemic Stroke. Ann. Neurol. 2011, 70, 59–69, doi:10.1002/ana.22458.
- Battistella, V.; de Freitas, G.R.; da Fonseca, L.M.B.; Mercante, D.; Gutfilen, B.; Goldenberg, R.C.; Dias, J.V.; Kasai-Brunswick, T.H.; Wajnberg, E.; Rosado-de-Castro, P.H.; et al. Safety of autologous bone marrow mononuclear cell transplantation in patients with nonacute ischemic stroke. Regen. Med. 2011, 6, 45–52, doi:10.2217/rme.10.97.
- Friedrich, M.A.G.; Martins, M.P.; Araujo, M.D.; Klamt, C.; Vedolin, L.; Garicochea, B.; Raupp, E.F.; El Ammar, J.S.; Machado, D.C.; da Costa, J.C.; et al. Intra-Arterial Infusion of Autologous Bone Marrow Mononuclear Cells in Patients With Moderate to Severe Middle Cerebral Artery Acute Ischemic Stroke. Cell Transplant. 2012, 21, S13–S21, doi:10.3727/096368912X612512.
- Zimmermann, S.; Voss, M.; Kaiser, S.; Kapp, U.; Waller, C.F.; Martens, U.M. Lack of telomerase activity in human mesenchymal stem cells. Leukemia 2003, 17, 1146–1149, doi:10.1038/sj.leu.2402962.
- Chopp, M.; Li, Y. Treatment of neural injury with marrow stromal cells. Lancet Neurol. 2002, 1, 92–100, doi:10.1016/S1474-4422(02)00040-6.
- Rempe, D.A.; Kent, T.A. Using bone marrow stromal cells for treatment of stroke. Neurology 2002, 59, 486–487, doi:10.1212/WNL.59.4.486.
- Song, S.; Kamath, S.; Mosquera, D.; Zigova, T.; Sanberg, P.; Vesely, D.L.; Sanchez-Ramos, J. Expression of brain natriuretic peptide by human bone marrow stromal cells. Exp. Neurol. 2004, 185, 191–197, doi:10.1016/j.expneurol.2003.09.003.
- Chen, J.; Li, Y.; Wang, L.; Lu, M.; Chopp, M. Caspase inhibition by Z-VAD increases the survival of grafted bone marrow cells and improves functional outcome after MCAo in rats. J. Neurol. Sci. 2002, 199, 17–24, doi:10.1016/S0022-510X(02)00075-8.
- Chen, J.; Li, Y.; Katakowski, M.; Chen, X.; Wang, L.; Lu, D.; Lu, M.; Gautam, S.C.; Chopp, M. Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J. Neurosci. Res. 2003, 73, 778–786, doi:10.1002/jnr.10691.
- Li, Y.; Chen, J.; Wang, L.; Lu, M.; Chopp, M. Treatment of stroke in rat with intracarotid administration of marrow stromal cells. Neurology 2001, 56, 1666–1672, doi:10.1212/WNL.56.12.1666.
- Zhang, J.; Li, Y.; Chen, J.; Yang, M.; Katakowski, M.; Lu, M.; Chopp, M. Expression of insulin-like growth factor 1 and receptor in ischemic rats treated with human marrow stromal cells. Brain Res. 2004, 1030, 19–27, doi:10.1016/j.brainres.2004.09.061.
- Crigler, L.; Robey, R.C.; Asawachaicharn, A.; Gaupp, D.; Phinney, D.G. Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis. Exp. Neurol. 2006, 198, 54–64, doi:10.1016/j.expneurol.2005.10.029.
- Lin, R.Z.; Moreno-Luna, R.; Zhou, B.; Pu, W.T.; Melero-Martin, J.M. Equal modulation of endothelial cell function by four distinct tissue-specific mesenchymal stem cells. Angiogenesis 2012, 15, 443–455, doi:10.1007/s10456-012-9272-2.
- Bang, O.Y.; Lee, J.S.; Lee, P.H.; Lee, G. Autologous mesenchymal stem cell transplantation in stroke patients. Ann. Neurol. 2005, 57, 874–882, doi:10.1002/ana.20501.
- Lee, J.S.; Hong, J.M.; Moon, G.J.; Lee, P.H.; Ahn, Y.H.; Bang, O.Y.; Collaborators, S. A Long-Term Follow-Up Study of Intravenous Autologous Mesenchymal Stem Cell Transplantation in Patients with Ischemic Stroke. Stem Cells 2010, 28, 1099–1106, doi:10.1002/stem.430.
- Dominici, M.; Le Blanc, K.; Mueller, I.; Slaper-Cortenbach, I.; Marini, F.; Krause, D.; Deans, R.; Keating, A.; Prockop, D.; Horwitz, E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006, 8, 315–317, doi:10.1080/14653240600855905.
- Barlow, S.; Brooke, G.; Chatterjee, K.; Price, G.; Pelekanos, R.; Rossetti, T.; Doody, M.; Venter, D.; Pain, S.; Gilshenan, K.; Atkinson, K. Comparison of human placenta- and bone marrow-derived multipotent mesenchymal stem cells. Stem Cells Dev. 2008, 17, 1095–1107, doi:10.1089/scd.2007.0154.
- Jansen, B.J.; Gilissen, C.; Roelofs, H.; Schaap-Oziemlak, A.; Veltman, J.A.; Raymakers, R.A.; Jansen, J.H.; Kogler, G.; Figdor, C.G.; Torensma, R.; Adema, G.J. Functional differences between mesenchymal stem cell populations are reflected by their transcriptome. Stem Cells Dev. 2010, 19, 481–490, doi:10.1089/scd.2009.0288.
- Kim, S.H.; Kim, Y.S.; Lee, S.Y.; Kim, K.H.; Lee, Y.M.; Kim, W.K.; Lee, Y.K. Gene expression profile in mesenchymal stem cells derived from dental tissues and bone marrow. J. Periodontal Implant Sci. 2011, 41, 192–200, doi:10.5051/jpis.2011.41.4.192.
- Dmitrieva, R.I.; Minullina, I.R.; Bilibina, A.A.; Tarasova, O.V.; Anisimov, S.V.; Zaritskey, A.Y. Bone marrow- and subcutaneous adipose tissue-derived mesenchymal stem cells: Differences and similarities. Cell Cycle 2012, 11, 377–383, doi:10.4161/cc.11.2.18858.
- Strioga, M.; Viswanathan, S.; Darinskas, A.; Slaby, O.; Michalek, J. Same or Not the Same? Comparison of Adipose Tissue-Derived versus Bone Marrow-Derived Mesenchymal Stem and Stromal Cells. Stem Cells Dev. 2012, 21, 2724–2752, doi:10.1089/scd.2011.0722.
- Vidal, M.A.; Walker, N.J.; Napoli, E.; Borjesson, D.L. Evaluation of senescence in mesenchymal stem cells isolated from equine bone marrow, adipose tissue, and umbilical cord tissue. Stem Cells Dev. 2012, 21, 273–283, doi:10.1089/scd.2010.0589.
- Tolar, J.; Nauta, A.J.; Osborn, M.J.; Panoskaltsis Mortari, A.; McElmurry, R.T.; Bell, S.; Xia, L.; Zhou, N.; Riddle, M.; Schroeder, T.M.; et al. Sarcoma derived from cultured mesenchymal stem cells. Stem Cells 2007, 25, 371–379, doi:10.1634/stemcells.2005-0620.
- De Luca, A.; Lamura, L.; Gallo, M.; Maffia, V.; Normanno, N. Mesenchymal stem cell-derived interleukin-6 and vascular endothelial growth factor promote breast cancer cell migration. J. Cell. Biochem. 2012, 113, 3363–3370, doi:10.1002/jcb.24212.
- Karnoub, A.E.; Dash, A.B.; Vo, A.P.; Sullivan, A.; Brooks, M.W.; Bell, G.W.; Richardson, A.L.; Polyak, K.; Tubo, R.; Weinberg, R.A. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007, 449, U557–U563.
- Subramanian, A.; Shu-Uin, G.; Kae-Siang, N.; Gauthaman, K.; Biswas, A.; Choolani, M.; Bongso, A.; Chui-Yee, F. Human umbilical cord Wharton’s jelly mesenchymal stem cells do not transform to tumor-associated fibroblasts in the presence of breast and ovarian cancer cells unlike bone marrow mesenchymal stem cells. J. Cell. Biochem. 2012, 113, 1886–1895, doi:10.1002/jcb.24057.
- Hristov, M.; Erl, W.; Weber, P.C. Endothelial progenitor cells: Mobilization, differentiation, and homing. Arterioscler. Thromb. Vasc. Biol. 2003, 23, 1185–1189, doi:10.1161/01.ATV.0000073832.49290.B5.
- Urbich, C.; Dimmeler, S. Endothelial progenitor cells: Characterization and role in vascular biology. Circ. Res. 2004, 95, 343–353, doi:10.1161/01.RES.0000137877.89448.78.
- Asahara, T.; Murohara, T.; Sullivan, A.; Silver, M.; van der Zee, R.; Li, T.; Witzenbichler, B.; Schatteman, G.; Isner, J.M. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997, 275, 964–967, doi:10.1126/science.275.5302.964.
- Kawamoto, A.; Losordo, D.W. Endothelial progenitor cells for cardiovascular regeneration. Trends Cardiovasc. Med. 2008, 18, 33–37, doi:10.1016/j.tcm.2007.11.004.
- Masuda, H.; Asahara, T. Post-natal endothelial progenitor cells for neovascularization in tissue regeneration. Cardiovasc. Res. 2003, 58, 390–398, doi:10.1016/S0008-6363(02)00785-X.
- Yip, H.K.; Chang, L.T.; Chang, W.N.; Lu, C.H.; Liou, C.W.; Lan, M.Y.; Liu, J.S.; Youssef, A.A.; Chang, H.W. Level and value of circulating endothelial progenitor cells in patients after acute ischemic stroke. Stroke 2008, 39, 69–74, doi:10.1161/STROKEAHA.107.489401.
- Chen, J.; Chen, S.Z.; Chen, Y.S.; Zhang, C.; Wang, J.J.; Zhang, W.F.; Liu, G.; Zhao, B.; Chen, Y.F. Circulating endothelial progenitor cells and cellular membrane microparticles in db/db diabetic mouse: Possible implications in cerebral ischemic damage. Am. J. Physiol. Endocrinol. Metab. 2011, 301, E62–E71, doi:10.1152/ajpendo.00026.2011.
- Chen, Z.Z.; Jiang, X.D.; Zhang, L.L.; Shang, J.H.; Du, M.X.; Xu, G.; Xu, R.X. Beneficial effect of autologous transplantation of bone marrow stromal cells and endothelial progenitor cells on cerebral ischemia in rabbits. Neurosci. Lett. 2008, 445, 36–41, doi:10.1016/j.neulet.2008.08.039.
- Kucia, M.; Reca, R.; Campbell, F.R.; Zuba-Surma, E.; Majka, M.; Ratajczak, J.; Ratajczak, M.Z. A population of very small embryonic-like (VSEL) CXCR4+SSEA-1+Oct-4+ stem cells identified in adult bone marrow. Leukemia 2006, 20, 857–869, doi:10.1038/sj.leu.2404171.
- Kucia, M.; Zhang, Y.P.; Reca, R.; Wysoczynski, M.; Machalinski, B.; Majka, M.; Ildstad, S.T.; Ratajczak, J.; Shields, C.B.; Ratajczak, M.Z. Cells enriched in markers of neural tissue-committed stem cells reside in the bone marrow and are mobilized into the peripheral blood following stroke. Leukemia 2006, 20, 18–28, doi:10.1038/sj.leu.2404011.
- Ratajczak, M.Z.; Kim, C.H.; Wojakowski, W.; Janowska-Wieczorek, A.; Kucia, M.; Ratajczak, J. Innate immunity as orchestrator of stem cell mobilization. Leukemia 2010, 24, 1667–1675, doi:10.1038/leu.2010.162.
- Paczkowska, E.; Kucia, M.; Koziarska, D.; Halasa, M.; Safranow, K.; Masiuk, M.; Karbicka, A.; Nowik, M.; Nowacki, P.; Ratajczak, M.Z.; Machalinski, B. Clinical Evidence That Very Small Embryonic-Like Stem Cells Are Mobilized Into Peripheral Blood in Patients After Stroke. Stroke 2009, 40, 1237–1244, doi:10.1161/STROKEAHA.108.535062.
- Ratajczak, M.Z.; Machalinski, B.; Wojakowski, W.; Ratajczak, J.; Kucia, M. A hypothesis for an embryonic origin of pluripotent Oct-4+ stem cells in adult bone marrow and other tissues. Leukemia 2007, 21, 860–867.
- Kucia, M.; Wysoczynski, M.; Ratajczak, J.; Ratajczak, M.Z. Identification of very small embryonic like (VSEL) stem cells in bone marrow. Cell Tissue Res. 2008, 331, 125–134, doi:10.1007/s00441-007-0485-4.
- Kucia, M.; Ratajczak, J.; Ratajczak, M.Z. Are bone marrow stem cells plastic or heterogenous—that is the question. Exp. Hematol. 2005, 33, 613–623, doi:10.1016/j.exphem.2005.01.016.
- Zuba-Surma, E.K.; Kucia, M.; Wu, W.; Klich, I.; Lillard, J.W., Jr.; Ratajczak, J.; Ratajczak, M.Z. Very small embryonic-like stem cells are present in adult murine organs: ImageStream-based morphological analysis and distribution studies. Cytometry A 2008, 73A, 1116–1127, doi:10.1002/cyto.a.20667.
- Ratajczak, J.; Shin, D.M.; Wan, W.; Liu, R.; Masternak, M.M.; Piotrowska, K.; Wiszniewska, B.; Kucia, M.; Bartke, A.; Ratajczak, M.Z. Higher number of stem cells in the bone marrow of circulating low Igf-1 level Laron dwarf mice—novel view on Igf-1, stem cells and aging. Leukemia 2011, 25, 729–733, doi:10.1038/leu.2010.314.
- Nakayama, D.; Matsuyama, T.; Ishibashi-Ueda, H.; Nakagomi, T.; Kasahara, Y.; Hirose, H.; Kikuchi-Taura, A.; Stern, D.M.; Mori, H.; Taguchi, A. Injury-induced neural stem/progenitor cells in post-stroke human cerebral cortex. Eur. J. Neurosci. 2010, 31, 90–98, doi:10.1111/j.1460-9568.2009.07043.x.
- Jin, K.; Sun, Y.J.; Xie, L.; Peel, A.; Mao, X.O.; Batteur, S.; Greenberg, D.A. Directed migration of neuronal precursors into the ischemic cerebral cortex and striatum. Mol. Cell. Neurosci. 2003, 24, 171–189, doi:10.1016/S1044-7431(03)00159-3.
- Thored, P.; Wood, J.; Arvidsson, A.; Cammenga, J.; Kokaia, Z.; Lindvall, O. Long-term neuroblast migration along blood vessels in an area with transient angiogenesis and increased vascularization after stroke. Stroke 2007, 38, 3032–3039, doi:10.1161/STROKEAHA.107.488445.
- Kojima, T.; Hirota, Y.; Ema, M.; Takahashi, S.; Miyoshi, I.; Okano, H.; Sawamoto, K. Subventricular zone-derived neural progenitor cells migrate along a blood vessel scaffold toward the post-stroke striatum. Stem Cells 2010, 28, 545–554.
- Barkho, B.Z.; Munoz, A.E.; Li, X.; Li, L.; Cunningham, L.A.; Zhao, X. Endogenous matrix metalloproteinase (MMP)-3 and MMP-9 promote the differentiation and migration of adult neural progenitor cells in response to chemokines. Stem Cells 2008, 26, 3139–3149, doi:10.1634/stemcells.2008-0519.
- Liu, X.S.; Chopp, M.; Zhang, R.L.; Hozeska-Solgot, A.; Gregg, S.C.; Buller, B.; Lu, M.; Zhang, Z.G. Angiopoietin 2 mediates the differentiation and migration of neural progenitor cells in the subventricular zone after stroke. J. Biol. Chem. 2009, 284, 22680–22689.
- Zhang, R.L.; Chopp, M.; Gregg, S.R.; Toh, Y.; Roberts, C.; Letourneau, Y.; Buller, B.; Jia, L.; Davarani, S.P.N.; Zhang, Z.G. Patterns and dynamics of subventricular zone neuroblast migration in the ischemic striatum of the adult mouse. J. Cereb. Blood Flow Metab. 2009, 29, 1240–1250, doi:10.1038/jcbfm.2009.55.
- Carbajal, K.S.; Schaumburg, C.; Strieter, R.; Kane, J.; Lane, T.E. Migration of engrafted neural stem cells is mediated by CXCL12 signaling through CXCR4 in a viral model of multiple sclerosis. Proc. Natl. Acad. Sci. USA 2010, 107, 11068–11073.
- Deierborg, T.; Roybon, L.; Inacio, A.R.; Pesic, J.; Brundin, P. Brain injury activates microglia that induce neural stem cell proliferation ex vivo and promote differentiation of neurosphere-derived cells into neurons and oligodendrocytes. Neuroscience 2010, 171, 1386–1396, doi:10.1016/j.neuroscience.2010.09.045.
- Arvidsson, A.; Collin, T.; Kirik, D.; Kokaia, Z.; Lindvall, O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat. Med. 2002, 8, 963–970.
- Nygren, J.; Wieloch, T.; Pesic, J.; Brundin, P.; Deierborg, T. Enriched environment attenuates cell genesis in subventricular zone after focal ischemia in mice and decreases migration of newborn cells to the striatum. Stroke 2006, 37, 2824–2829, doi:10.1161/01.STR.0000244769.39952.90.
- Deierborg, T.; Staflin, K.; Pesic, J.; Roybon, L.; Brundin, P.; Lundberg, C. Absence of striatal newborn neurons with mature phenotype following defined striatal and cortical excitotoxic brain injuries. Exp. Neurol. 2009, 219, 363–367, doi:10.1016/j.expneurol.2009.05.002.
- Park, D.H.; Eve, D.J.; Sanberg, P.R.; Musso, J., III; Bachstetter, A.D.; Wolfson, A.; Schlunk, A.; Baradez, M.O.; Sinden, J.D.; Gemma, C. Increased neuronal proliferation in the dentate gyrus of aged rats following neural stem cell implantation. Stem Cells Dev. 2010, 19, 175–180, doi:10.1089/scd.2009.0172.
- Jin, K.; Xie, L.; Mao, X.; Greenberg, M.B.; Moore, A.; Peng, B.; Greenberg, R.B.; Greenberg, D.A. Effect of human neural precursor cell transplantation on endogenous neurogenesis after focal cerebral ischemia in the rat. Brain Res. 2011, 1374, 56–62, doi:10.1016/j.brainres.2010.12.037.
- Minnerup, J.; Kim, J.B.; Schmidt, A.; Diederich, K.; Bauer, H.; Schilling, M.; Strecker, J.K.; Ringelstein, E.B.; Sommer, C.; Scholer, H.R.; Schabitz, W.R. Effects of neural progenitor cells on sensorimotor recovery and endogenous repair mechanisms after photothrombotic stroke. Stroke 2011, 42, 1757–1763, doi:10.1161/STROKEAHA.110.599282.
- Stroemer, P.; Patel, S.; Hope, A.; Oliveira, C.; Pollock, K.; Sinden, J. The Neural Stem Cell Line CTX0E03 Promotes Behavioral Recovery and Endogenous Neurogenesis after Experimental Stroke in a Dose-Dependent Fashion. Neurorehab. Neural Repair 2009, 23, 895–909, doi:10.1177/1545968309335978.
- Daadi, M.M.; Li, Z.; Arac, A.; Grueter, B.A.; Sofilos, M.; Malenka, R.C.; Wu, J.C.; Steinberg, G.K. Molecular and magnetic resonance imaging of human embryonic stem cell-derived neural stem cell grafts in ischemic rat brain. Mol. Ther. 2009, 17, 1282–1291, doi:10.1038/mt.2009.104.
- Chaichana, K.L.; Guerrero-Cazares, H.; Capilla-Gonzalez, V.; Zamora-Berridi, G.; Achanta, P.; Gonzalez-Perez, O.; Jallo, G.I.; Garcia-Verdugo, J.M.; Quinones-Hinojosa, A. Intra-operatively obtained human tissue: Protocols and techniques for the study of neural stem cells. J. Neurosci. Methods 2009, 180, 116–125, doi:10.1016/j.jneumeth.2009.02.014.
- Jandial, R.; Snyder, E.Y. A safer stem cell: On guard against cancer. Nat. Med. 2009, 15, 999–1001, doi:10.1038/nm0909-999.
- Amariglio, N.; Rechavi, G. On the origin of glioneural neoplasms after neural cell transplantation. Nat. Med. 2010, 16, 157; author reply 157–158.
- Amariglio, N.; Hirshberg, A.; Scheithauer, B.W.; Cohen, Y.; Loewenthal, R.; Trakhtenbrot, L.; Paz, N.; Koren-Michowitz, M.; Waldman, D.; Leider-Trejo, L.; et al. Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med. 2009, 6, e1000029.
- Wu, W.; He, Q.; Li, X.; Zhang, X.; Lu, A.; Ge, R.; Zhen, H.; Chang, A.E.; Li, Q.; Shen, L. Long-term cultured human neural stem cells undergo spontaneous transformation to tumor-initiating cells. Int. J. Biol. Sci. 2011, 7, 892–901.
- Newman, M.B.; Misiuta, I.; Willing, A.E.; Zigova, T.; Karl, R.C.; Borlongan, C.V.; Sanberg, P.R. Tumorigenicity issues of embryonic carcinoma-derived stem cells: Relevance to surgical trials using NT2 and hNT neural cells. Stem Cells Dev. 2005, 14, 29–43, doi:10.1089/scd.2005.14.29.
- Kondziolka, D.; Steinberg, G.K.; Wechsler, L.; Meltzer, C.C.; Elder, E.; Gebel, J.; Decesare, S.; Jovin, T.; Zafonte, R.; Lebowitz, J.; et al. Neurotransplantation for patients with subcortical motor stroke: A phase 2 randomized trial. J. Neurosurg. 2005, 103, 38–45, doi:10.3171/jns.2005.103.1.0038.
- Pollock, K.; Stroemer, P.; Patel, S.; Stevanato, L.; Hope, A.; Miljan, E.; Dong, Z.; Hodges, H.; Price, J.; Sinden, J.D. A conditionally immortal clonal stem cell line from human cortical neuroepithelium for the treatment of ischemic stroke. Exp. Neurol. 2006, 199, 143–155, doi:10.1016/j.expneurol.2005.12.011.
- Mack, G.S. ReNeuron and StemCells get green light for neural stem cell trials. Nat. Biotechnol. 2011, 29, 95–97.
- Marcus, A.J.; Woodbury, D. Fetal stem cells from extra-embryonic tissues: Do not discard. J. Cell. Mol. Med. 2008, 12, 730–742, doi:10.1111/j.1582-4934.2008.00221.x.
- Yu, S.J.; Soncini, M.; Kaneko, Y.; Hess, D.C.; Parolini, O.; Borlongan, C.V. Amnion: A potent graft source for cell therapy in stroke. Cell Transplant. 2009, 18, 111–118, doi:10.3727/096368909788341243.
- Diaz-Prado, S.; Muinos-Lopez, E.; Hermida-Gomez, T.; Rendal-Vazquez, M.E.; Fuentes-Boquete, I.; de Toro, F.J.; Blanco, F.J. Multilineage differentiation potential of cells isolated from the human amniotic membrane. J. Cell. Biochem. 2010, 111, 846–857.
- Konig, J.; Huppertz, B.; Desoye, G.; Parolini, O.; Frohlich, J.D.; Weiss, G.; Dohr, G.; Sedlmayr, P.; Lang, I. Amnion-derived mesenchymal stromal cells show angiogenic properties but resist differentiation into mature endothelial cells. Stem Cells Dev. 2012, 21, 1309–1320, doi:10.1089/scd.2011.0223.
- Yarygin, K.N.; Kholodenko, I.V.; Konieva, A.A.; Burunova, V.V.; Tairova, R.T.; Gubsky, L.V.; Cheglakov, I.B.; Pirogov, Y.A.; Yarygin, V.N.; Skvortsova, V.I. Mechanisms of positive effects of transplantation of human placental mesenchymal stem cells on recovery of rats after experimental ischemic stroke. Bull. Exp. Biol. Med. 2009, 148, 862–868.
- Chen, J.; Shehadah, A.; Pal, A.; Zacharek, A.; Cui, X.; Cui, Y.; Roberts, C.; Lu, M.; Zeitlin, A.; Hariri, R.; Chopp, M. Neuroprotective effect of human placenta-derived cell treatment of stroke in rats. Cell Transplant. 2012. in press.
- Kranz, A.; Wagner, D.C.; Kamprad, M.; Scholz, M.; Schmidt, U.R.; Nitzsche, F.; Aberman, Z.; Emmrich, F.; Riegelsberger, U.M.; Boltze, J. Transplantation of placenta-derived mesenchymal stromal cells upon experimental stroke in rats. Brain Res. 2010, 1315, 128–136, doi:10.1016/j.brainres.2009.12.001.
- Liao, W.B.; Xie, J.; Zhong, J.; Liu, Y.J.; Du, L.; Zhou, B.; Xu, J.; Liu, P.X.; Yang, S.G.; Wang, J.M.; et al. Therapeutic Effect of Human Umbilical Cord Multipotent Mesenchymal Stromal Cells in a Rat Model of Stroke. Transplantation 2009, 87, 350–359.
- Deuse, T.; Stubbendorff, M.; Tang-Quan, K.; Phillips, N.; Kay, M.A.; Eiermann, T.; Phan, T.T.; Volk, H.D.; Reichenspurner, H.; Robbins, R.C.; Schrepfer, S. Immunogenicity and immunomodulatory properties of umbilical cord lining mesenchymal stem cells. Cell Transplant. 2011, 20, 655–667, doi:10.3727/096368910X536473.
- Ding, D.C.; Shyu, W.C.; Chiang, M.F.; Lin, S.Z.; Chang, Y.C.; Wang, H.J.; Su, C.Y.; Li, H. Enhancement of neuroplasticity through upregulation of beta 1-integrin in human umbilical cord-derived stromal cell implanted stroke model. Neurobiol. Dis. 2007, 27, 339–353, doi:10.1016/j.nbd.2007.06.010.
- Najar, M.; Raicevic, G.; Boufker, H.I.; Fayyad-Kazan, H.; De Bruyn, C.; Meuleman, N.; Bron, D.; Toungouz, M.; Lagneaux, L. Adipose-tissue-derived and Wharton’s jelly-derived mesenchymal stromal cells suppress lymphocyte responses by secreting leukemia inhibitory factor. Tissue Eng. Part A 2010, 16, 3537–3546, doi:10.1089/ten.tea.2010.0159.
- Vendrame, M.; Gemma, C.; de Mesquita, D.; Collier, L.; Bickford, P.C.; Sanberg, C.D.; Sanberg, P.R.; Pennypacker, K.R.; Willing, A.E. Anti-inflammatory effects of human cord blood cells in a rat model of stroke. Stem Cells Dev. 2005, 14, 595–604, doi:10.1089/scd.2005.14.595.
- Xiao, J.; Nan, Z.H.; Motooka, Y.; Low, W.C. Transplantation of a novel cell line population of umbilical cord blood stem cells ameliorates neurological deficits associated with ischemic brain injury. Stem Cells Dev. 2005, 14, 722–733, doi:10.1089/scd.2005.14.722.
- Chung, D.J.; Choi, C.B.; Lee, S.H.; Kang, E.H.; Lee, J.H.; Hwang, S.H.; Han, H.; Lee, J.H.; Choe, B.Y.; Lee, S.Y.; Kim, H.Y. Intraarterially Delivered Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells in Canine Cerebral Ischemia. J. Neurosci. Res. 2009, 87, 3554–3567, doi:10.1002/jnr.22162.
- Gimble, J.M.; Katz, A.J.; Bunnell, B.A. Adipose-derived stem cells for regenerative medicine. Circ. Res. 2007, 100, 1249–1260, doi:10.1161/01.RES.0000265074.83288.09.
- Kim, J.M.; Lee, S.T.; Chu, K.; Jung, K.H.; Song, E.C.; Kim, S.J.; Sinn, D.I.; Kim, J.H.; Park, D.K.; Kang, K.M.; et al. Systemic transplantation of human adipose stem cells attenuated cerebral inflammation and degeneration in a hemorrhagic stroke model. Brain Res. 2007, 1183, 43–50.
- Leu, S.; Lin, Y.C.; Yuen, C.M.; Yen, C.H.; Kao, Y.H.; Sun, C.K.; Yip, H.K. Adipose-derived mesenchymal stem cells markedly attenuate brain infarct size and improve neurological function in rats. J. Transl. Med. 2010, 8, 63, doi:10.1186/1479-5876-8-63.
- Ikegame, Y.; Yamashita, K.; Hayashi, S.I.; Mizuno, H.; Tawada, M.; You, F.; Yamada, K.; Tanaka, Y.; Egashira, Y.; Nakashima, S.; Yoshimura, S.I.; Iwama, T. Comparison of mesenchymal stem cells from adipose tissue and bone marrow for ischemic stroke therapy. Cytotherapy 2011, 13, 675–685, doi:10.3109/14653249.2010.549122.
- Rubio, D.; Garcia-Castro, J.; Martin, M.C.; de la Fuente, R.; Cigudosa, J.C.; Lloyd, A.C.; Bernad, A. Spontaneous human adult stem cell transformation. Cancer Res. 2005, 65, 3035–3039.
- de la Fuente, R.; Bernad, A.; Garcia-Castro, J.; Martin, M.C.; Cigudosa, J.C. Retraction: Spontaneous human adult stem cell transformation. Cancer Res. 2010, 70, 6682.
- Ra, J.C.; Shin, I.S.; Kim, S.H.; Kang, S.K.; Kang, B.C.; Lee, H.Y.; Kim, Y.J.; Jo, J.Y.; Yoon, E.J.; Choi, H.J.; Kwon, E. Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem cells in animals and humans. Stem Cells Dev. 2011, 20, 1297–1308, doi:10.1089/scd.2010.0466.
- Meng, X.; Ichim, T.E.; Zhong, J.; Rogers, A.; Yin, Z.; Jackson, J.; Wang, H.; Ge, W.; Bogin, V.; Chan, K.W.; Thebaud, B.; Riordan, N.H. Endometrial regenerative cells: A novel stem cell population. J. Transl. Med. 2007, 5, 57, doi:10.1186/1479-5876-5-57.
- Patel, A.N.; Park, E.; Kuzman, M.; Benetti, F.; Silva, F.J.; Allickson, J.G. Multipotent menstrual blood stromal stem cells: Isolation, characterization, and differentiation. Cell Transplant. 2008, 17, 303–311, doi:10.3727/096368908784153922.
- Borlongan, C.V.; Kaneko, Y.; Maki, M.; Yu, S.J.; Ali, M.; Allickson, J.G.; Sanberg, C.D.; Kuzmin-Nichols, N.; Sanberg, P.R. Menstrual blood cells display stem cell-like phenotypic markers and exert neuroprotection following transplantation in experimental stroke. Stem Cells Dev. 2010, 19, 439–452, doi:10.1089/scd.2009.0340.
- Allickson, J.G.; Sanchez, A.; Yefimenko, N.; Borlongan, C.V.; Sanberg, P.R. Recent Studies Assessing the Proliferative Capability of a Novel Adult Stem Cell Identified in Menstrual Blood. Open Stem Cell J. 2011, 3, 4–10.
- Rodrigues, M.C.; Voltarelli, J.; Sanberg, P.R.; Allickson, J.G.; Kuzmin-Nichols, N.; Garbuzova-Davis, S.; Borlongan, C.V. Recent progress in cell therapy for basal ganglia disorders with emphasis on menstrual blood transplantation in stroke. Neurosci. Biobehav. Rev. 2012, 36, 177–190, doi:10.1016/j.neubiorev.2011.05.010.
- Cregan, M.D.; Fan, Y.P.; Appelbee, A.; Brown, M.L.; Klopcic, B.; Koppen, J.; Mitoulas, L.R.; Piper, K.M.E.; Choolani, M.A.; Chong, Y.S.; Hartmann, P.E. Identification of nestin-positive putative mammary stem cells in human breastmilk. Cell Tissue Res. 2007, 329, 129–136, doi:10.1007/s00441-007-0390-x.
- Hassiotou, F.; Beltran, A.; Chetwynd, E.; Stuebe, A.M.; Twigger, A.J.; Metzger, P.; Trengove, N.; Lai, C.T.; Filgueira, L.; Blancafort, P.; Hartmann, P.E. Breastmilk Is a Novel Source of Stem Cells with Multilineage Differentiation Potential. Stem Cells 2012, 30, 2164–2174, doi:10.1002/stem.1188.
- McGregor, J.A.; Rogo, L.J. Breast milk: An unappreciated source of stem cells. J. Hum. Lact. 2006, 22, 270–271, doi:10.1177/0890334406290222.
- Gronthos, S.; Mankani, M.; Brahim, J.; Robey, P.G.; Shi, S. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc. Natl. Acad. Sci. USA 2000, 97, 13625–13630.
- Seo, B.M.; Miura, M.; Gronthos, S. Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet 2004, 364, 149–155.
- Sonoyama, W.; Liu, Y.; Fang, D.A.J.; Yamaza, T.; Seo, B.M.; Zhang, C.M.; Liu, H.; Gronthos, S.; Wang, C.Y.; Shi, S.T.; Wang, S.L. Mesenchymal Stem Cell-Mediated Functional Tooth Regeneration in Swine. PloS One 2006, 1, e79.
- Sonoyama, W.; Liu, Y.; Yamaza, T.; Tuan, R.S.; Wang, S.; Shi, S.; Huang, G.T.J. Characterization of the apical papilla and its residing stem cells from human immature permanent teeth: A pilot study. J. Endod. 2008, 34, 166–171, doi:10.1016/j.joen.2007.11.021.
- Morsczeck, C.; Gotz, W.; Schierholz, J.; Zellhofer, F.; Kuhn, U.; Mohl, C.; Sippel, C.; Hoffmann, K.H. Isolation of precursor cells (PCs) from human dental follicle of wisdom teeth. Matrix Biol. 2005, 24, 155–165, doi:10.1016/j.matbio.2004.12.004.
- Huang, G.T.J.; Gronthos, S.; Shi, S. Mesenchymal Stem Cells Derived from Dental Tissues vs. Those from Other Sources: Their Biology and Role in Regenerative Medicine. J. Dent. Res. 2009, 88, 792–806, doi:10.1177/0022034509340867.
- Miura, M.; Gronthos, S.; Zhao, M.; Lu, B.; Fisher, L.W.; Robey, P.G.; Shi, S. SHED: Stem cells from human exfoliated deciduous teeth. Proc. Natl. Acad. Sci. USA 2003, 100, 5807–5812.
- Yang, K.L.; Chen, M.F.; Liao, C.H.; Pang, C.Y.; Lin, P.Y. A simple and efficient method for generating Nurr1-positive neuronal stem cells from human wisdom teeth (tNSC) and the potential of tNSC for stroke therapy. Cytotherapy 2009, 11, 606–617, doi:10.1080/14653240902806994.
- Leong, W.K.; Henshall, T.L.; Arthur, A.; Kremer, K.L.; Lewis, M.D.; Helps, S.C.; Field, J.; Hamilton-Bruce, M.A.; Warming, S.; Manavis, J.; et al. Human Adult Dental Pulp Stem Cells Enhance Poststroke Functional Recovery through Non-Neural Replacement Mechanisms. Stem Cells Transl. Med. 2012, 1, 177–187, doi:10.5966/sctm.2011-0039.
- Karaoz, E.; Demircan, P.C.; Saglam, O.; Aksoy, A.; Kaymaz, F.; Duruksu, G. Human dental pulp stem cells demonstrate better neural and epithelial stem cell properties than bone marrow-derived mesenchymal stem cells. Histochem. Cell Biol. 2011, 136, 455–473, doi:10.1007/s00418-011-0858-3.
- Takahashi, K.; Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006, 126, 663–676, doi:10.1016/j.cell.2006.07.024.
- Cai, J.; Li, W.; Su, H.; Qin, D.; Yang, J.; Zhu, F.; Xu, J.; He, W.; Guo, X.; Labuda, K.; et al. Generation of human induced pluripotent stem cells from umbilical cord matrix and amniotic membrane mesenchymal cells. J. Biol. Chem. 2010, 285, 11227–11234.
- Tat, P.A.; Sumer, H.; Jones, K.L.; Upton, K.; Verma, P.J. The efficient generation of induced pluripotent stem (iPS) cells from adult mouse adipose tissue-derived and neural stem cells. Cell Transplant. 2010, 19, 525–536, doi:10.3727/096368910X491374.
- Chen, S.J.; Chang, C.M.; Tsai, S.K.; Chang, Y.L.; Chou, S.J.; Huang, S.S.; Tai, L.K.; Chen, Y.C.; Ku, H.H.; Li, H.Y.; Chiou, S.H. Functional Improvement of Focal Cerebral Ischemia Injury by Subdural Transplantation of Induced Pluripotent Stem Cells with Fibrin Glue. Stem Cells Dev. 2010, 19, 1757–1767, doi:10.1089/scd.2009.0452.
- Jiang, M.; Lv, L.; Ji, H.; Yang, X.; Zhu, W.; Cai, L.; Gu, X.; Chai, C.; Huang, S.; Sun, J.; Dong, Q. Induction of pluripotent stem cells transplantation therapy for ischemic stroke. Mol. Cell. Biochem. 2011, 354, 67–75, doi:10.1007/s11010-011-0806-5.
- Zhao, T.; Zhang, Z.N.; Rong, Z.; Xu, Y. Immunogenicity of induced pluripotent stem cells. Nature 2011, 474, 212–215, doi:10.1038/nature10135.
- Kawai, H.; Yamashita, T.; Ohta, Y.; Deguchi, K.; Nagotani, S.; Zhang, X.M.; Ikeda, Y.; Matsuura, T.; Abe, K. Tridermal tumorigenesis of induced pluripotent stem cells transplanted in ischemic brain. J. Cereb. Blood Flow Metab. 2010, 30, 1487–1493, doi:10.1038/jcbfm.2010.32.
- Yamashita, T.; Kawai, H.; Tian, F.F.; Ohta, Y.; Abe, K. Tumorigenic Development of Induced Pluripotent Stem Cells in Ischemic Mouse Brain. Cell Transplant. 2011, 20, 883–891, doi:10.3727/096368910X539092.
- Oki, K.; Tatarishvili, J.; Wood, J.; Koch, P.; Wattananit, S.; Mine, Y.; Monni, E.; Tornero, D.; Ahlenius, H.; Ladewig, J.; et al. Human-Induced Pluripotent Stem Cells form Functional Neurons and Improve Recovery after Grafting in Stroke-Damaged Brain. Stem Cells 2012, 30, 1120–1133, doi:10.1002/stem.1104.
- Oh, J.S.; Kim, K.N.; An, S.S.; Pennant, W.A.; Kim, H.J.; Gwak, S.J.; Yoon do, H.; Lim, M.H.; Choi, B.H.; Ha, Y. Cotransplantation of mouse neural stem cells (mNSCs) with adipose tissue-derived mesenchymal stem cells improves mNSC survival in a rat spinal cord injury model. Cell Transplant. 2011, 20, 837–849, doi:10.3727/096368910X539083.
- Matsuda, R.; Yoshikawa, M.; Kimura, H.; Ouji, Y.; Nakase, H.; Nishimura, F.; Nonaka, J.; Toriumi, H.; Yamada, S.; Nishiofuku, M.; et al. Cotransplantation of mouse embryonic stem cells and bone marrow stromal cells following spinal cord injury suppresses tumor development. Cell Transplant. 2009, 18, 39–54, doi:10.3727/096368909788237122.
- Nakagomi, N.; Nakagomi, T.; Kubo, S.; Nakano-Doi, A.; Saino, O.; Takata, M.; Yoshikawa, H.; Stern, D.M.; Matsuyama, T.; Taguchi, A. Endothelial cells support survival, proliferation, and neuronal differentiation of transplanted adult ischemia-induced neural stem/progenitor cells after cerebral infarction. Stem Cells 2009, 27, 2185–2195, doi:10.1002/stem.161.
- Zhang, W.; Yan, Q.; Zeng, Y.S.; Zhang, X.B.; Xiong, Y.; Wang, J.M.; Chen, S.J.; Li, Y.; Bruce, I.C.; Wu, W. Implantation of adult bone marrow-derived mesenchymal stem cells transfected with the neurotrophin-3 gene and pretreated with retinoic acid in completely transected spinal cord. Brain Res. 2010, 1359, 256–271, doi:10.1016/j.brainres.2010.08.072.
- Jin, K.; Mao, X.; Xie, L.; Galvan, V.; Lai, B.; Wang, Y.; Gorostiza, O.; Wang, X.; Greenberg, D.A. Transplantation of human neural precursor cells in Matrigel scaffolding improves outcome from focal cerebral ischemia after delayed postischemic treatment in rats. J. Cereb. Blood Flow Metab. 2010, 30, 534–544, doi:10.1038/jcbfm.2009.219.
- Sanberg, P.R.; Eve, D.J.; Cruz, L.E.; Borlongan, C.V. Neurological disorders and the potential role for stem cells as a therapy. Br. Med. Bull. 2012, 101, 163–181.
- Borlongan, C.V.; Chopp, M.; Steinberg, G.K.; Bliss, T.M.; Li, Y.; Lu, M.; Hess, D.C.; Kondziolka, D. Potential of stem/progenitor cells in treating stroke: the missing steps in translating cell therapy from laboratory to clinic. Regen. Med. 2008, 3, 249–250, doi:10.2217/17460718.104.22.168.
- Borlongan, C.V. Cell therapy for stroke: remaining issues to address before embarking on clinical trials. Stroke 2009, 40, S146–S148, doi:10.1161/STROKEAHA.108.533091.
- Chopp, M.; Steinberg, G.K.; Kondziolka, D.; Lu, M.; Bliss, T.M.; Li, Y.; Hess, D.C.; Borlongan, C.V. Who’s in favor of translational cell therapy for stroke: STEPS forward please? Cell Transplant. 2009, 18, 691–693, doi:10.3727/096368909X470883.
- Borlongan, C.V.; Weiss, M.D. Baby STEPS: A giant leap for cell therapy in neonatal brain injury. Pediatr. Res. 2011, 70, 3–9, doi:10.1203/PDR.0b013e31821d0d00.
© 2013 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).