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Special Issue "Frontiers in Stem Cell Treatments"

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383).

Deadline for manuscript submissions: closed (30 June 2013)

Special Issue Editor

Guest Editor
Prof. Dr. Frank Barry (Website)

Regenerative Medicine Institute (REMEDI), National Centre of Biomedical Engineering Science(NCBES), National University of Ireland, Galway, Ireland
Interests: biology of adult stem cells; tissue engineering; cell transplantation protocols; immunology of allogeneic cell transplantation; gene therapy; cell-based gene delivery; regulation of differentiation; mechanisms of engraftment and homing of transplanted stem cells; stem cell plasticity

Special Issue Information

Dear Colleagues,

There has been a great deal of interest in recent years in the use of stem cells in the treatment of a broad spectrum of diseases and many predictions have been made which suggest that the future practice of medicine will rely heavily on applications in stem cell technology. There has been steady progress in understanding the biological nature of stem cells, their isolation and expansion, and how they make fate decisions. One of the most significant steps has been the demonstration that mature somatic cells can be reprogrammed to become pluripotent. Indeed, the development of induced pluripotent stem (iPS) cell technology has opened doors into an extraordinary world of new understanding and clinical potential. This great achievement has been justly recognized by the award of the 2012 Nobel Prize in Physiology or Medicine to Sir John B. Gurdon and Shinya Yamanaka.
In addition to progress in understanding the fundamental nature of stem cells, there has also been an explosion of preclinical studies. These have been overwhelmingly positive and have, in study after study, pointed to the therapeutic promise of stem cells. They have taught us about the potential roles of stem cells in tissue regeneration, modulation of the immune system and paracrine mechanisms to stimulate a host response. Nonetheless, the clinical testing of stem cells in controlled, randomized trials has moved at a slow pace and for some the proof of concept is yet to be fully delivered.
There are many obstacles on the road to clinical testing, not least being an understanding of toxicology, mechanism of action and large scale expansion. The current special issue is designed to examine the clinical potential of stem cell therapy and provide a timely update on the current status of clinical trials.

Prof. Dr. Frank Barry
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 300 CHF (Swiss Francs). English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.

Keywords

  • stem cells
  • regenerative medicine
  • clinical trials
  • immunomodulation
  • paracrine effects
  • pluripotency
  • mesenchymal stem cells

Published Papers (10 papers)

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Research

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Open AccessArticle Aging Impairs the Proliferative Capacity of Cardiospheres, Cardiac Progenitor Cells and Cardiac Fibroblasts: Implications for Cell Therapy
J. Clin. Med. 2013, 2(3), 103-114; doi:10.3390/jcm2030103
Received: 31 July 2013 / Revised: 9 August 2013 / Accepted: 22 August 2013 / Published: 23 September 2013
Cited by 1 | PDF Full-text (1078 KB) | HTML Full-text | XML Full-text
Abstract
Introduction: Cardiospheres (CS) are self-assembling clusters of cells that can be grown from cardiac tissue. They contain a heterogeneous cell population that includes cardiac progenitor cells (CPCs) and cardiac fibroblasts. CS and CPCs have been shown to improve cardiac function after myocardial [...] Read more.
Introduction: Cardiospheres (CS) are self-assembling clusters of cells that can be grown from cardiac tissue. They contain a heterogeneous cell population that includes cardiac progenitor cells (CPCs) and cardiac fibroblasts. CS and CPCs have been shown to improve cardiac function after myocardial infarction (MI) in experimental models and are now being studied in clinical trials. The effects of aging on the proliferative capacity of CS and CPCs, and the paracrine signaling between cell types, remain incompletely understood. Methods and Results: We compared the growth of CS from young and aging murine hearts at baseline and following MI. The number of CS from young and aging hearts was similar at baseline. However, after MI, young hearts had a dramatic increase in the number of CS that grew, but this proliferative response to MI was virtually abolished in the aging heart. Further, the proportion of cells within the CS that were CPCs (defined as Sca-1(stem cell antigen-1)+/CD45) was significantly lower in aging hearts than young hearts. Thus the number of available CPCs after culture from aging hearts was substantially lower than from young hearts. Cardiac fibroblasts from aging hearts proliferated more slowly in culture than those from young hearts. We then investigated the interaction between aging cardiac fibroblasts and CPCs. We found no significant paracrine effects on proliferation between these cell types, suggesting the impaired proliferation is a cell-autonomous problem. Conclusions: Aging hearts generate fewer CPCs, and aging CPCs have significantly reduced proliferative potential following MI. Aging cardiac fibroblasts also have reduced proliferative capacity, but these appear to be cell-autonomous problems, not caused by paracrine signaling between cell types. Full article
(This article belongs to the Special Issue Frontiers in Stem Cell Treatments)
Open AccessArticle Engraftment Outcomes after HPC Co-Culture with Mesenchymal Stromal Cells and Osteoblasts
J. Clin. Med. 2013, 2(3), 115-135; doi:10.3390/jcm2030115
Received: 25 July 2013 / Revised: 22 August 2013 / Accepted: 10 September 2013 / Published: 23 September 2013
Cited by 2 | PDF Full-text (1542 KB) | HTML Full-text | XML Full-text
Abstract
Haematopoietic stem cell (HSC) transplantation is an established cell-based therapy for a number of haematological diseases. To enhance this therapy, there is considerable interest in expanding HSCs in artificial niches prior to transplantation. This study compared murine HSC expansion supported through co-culture [...] Read more.
Haematopoietic stem cell (HSC) transplantation is an established cell-based therapy for a number of haematological diseases. To enhance this therapy, there is considerable interest in expanding HSCs in artificial niches prior to transplantation. This study compared murine HSC expansion supported through co-culture on monolayers of either undifferentiated mesenchymal stromal cells (MSCs) or osteoblasts. Sorted Lineage Sca-1+ c-kit+ (LSK) haematopoietic stem/progenitor cells (HPC) demonstrated proliferative capacity on both stromal monolayers with the greatest expansion of LSK shown in cultures supported by osteoblast monolayers. After transplantation, both types of bulk-expanded cultures were capable of engrafting and repopulating lethally irradiated primary and secondary murine recipients. LSKs co-cultured on MSCs showed comparable, but not superior, reconstitution ability to that of freshly isolated LSKs. Surprisingly, however, osteoblast co-cultured LSKs showed significantly poorer haematopoietic reconstitution compared to LSKs co-cultured on MSCs, likely due to a delay in short-term reconstitution. We demonstrated that stromal monolayers can be used to maintain, but not expand, functional HSCs without a need for additional haematopoietic growth factors. We also demonstrated that despite apparently superior in vitro performance, co-injection of bulk cultures of osteoblasts and LSKs in vivo was detrimental to recipient survival and should be avoided in translation to clinical practice. Full article
(This article belongs to the Special Issue Frontiers in Stem Cell Treatments)
Open AccessArticle Short Term Culture of Human Mesenchymal Stem Cells with Commercial Osteoconductive Carriers Provides Unique Insights into Biocompatibility
J. Clin. Med. 2013, 2(3), 49-66; doi:10.3390/jcm2030049
Received: 30 May 2013 / Revised: 6 July 2013 / Accepted: 9 July 2013 / Published: 19 August 2013
Cited by 3 | PDF Full-text (917 KB) | HTML Full-text | XML Full-text
Abstract
For spinal fusions and the treatment of non-union fractures, biological substrates, scaffolds, or carriers often are applied as a graft to support regeneration of bone. The selection of an appropriate material critically influences cellular function and, ultimately, patient outcomes. Human bone marrow [...] Read more.
For spinal fusions and the treatment of non-union fractures, biological substrates, scaffolds, or carriers often are applied as a graft to support regeneration of bone. The selection of an appropriate material critically influences cellular function and, ultimately, patient outcomes. Human bone marrow mesenchymal stem cells (BMSCs) are regarded as a critical component of bone healing. However, the interactions of BMSCs and commercial bone matrices are poorly reported. BMSCs were cultured with several commercially available bone substrates (allograft, demineralized bone matrix (DBM), collagen, and various forms of calcium phosphates) for 48 h to understand their response to graft materials during surgical preparation and the first days following implantation (cell retention, gene expression, pH). At 30 and 60 min, bone chips and inorganic substrates supported significantly more cell retention than other materials, while collagen-containing materials became soluble and lost their structure. At 48 h, cells bound to β-tricalcium phosphate-hydroxyapatite (βTCP-HA) and porous hydroxyapatite (HA) granules exhibited osteogenic gene expression statistically similar to bone chips. Through 24 h, the DBM strip and βTCP-collagen became mildly acidic (pH 7.1–7.3), while the DBM poloxamer-putties demonstrated acidity (pH < 5) and the bioglass-containing carrier became basic (pH > 10). The dissolution of DBM and collagen led to a loss of cells, while excessive pH changes potentially diminish cell viability and metabolism. Extracts from DBM-poloxamers induced osteogenic gene expression at 48 h. This study highlights the role that biochemical and structural properties of biomaterials play in cellular function, potentially enhancing or diminishing the efficacy of the overall therapy. Full article
(This article belongs to the Special Issue Frontiers in Stem Cell Treatments)

Review

Jump to: Research

Open AccessReview The Power and the Promise of Cell Reprogramming: Personalized Autologous Body Organ and Cell Transplantation
J. Clin. Med. 2014, 3(2), 373-387; doi:10.3390/jcm3020373
Received: 14 January 2014 / Revised: 17 February 2014 / Accepted: 19 February 2014 / Published: 4 April 2014
PDF Full-text (241 KB) | HTML Full-text | XML Full-text
Abstract
Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) or direct reprogramming to desired cell types are powerful and new in vitro methods for the study of human disease, cell replacement therapy, and drug development. Both methods to reprogram cells are unconstrained [...] Read more.
Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) or direct reprogramming to desired cell types are powerful and new in vitro methods for the study of human disease, cell replacement therapy, and drug development. Both methods to reprogram cells are unconstrained by the ethical and social questions raised by embryonic stem cells. iPSC technology promises to enable personalized autologous cell therapy and has the potential to revolutionize cell replacement therapy and regenerative medicine. Potential applications of iPSC technology are rapidly increasing in ambition from discrete cell replacement applications to the iPSC assisted bioengineering of body organs for personalized autologous body organ transplant. Recent work has demonstrated that the generation of organs from iPSCs is a future possibility. The development of embryonic-like organ structures bioengineered from iPSCs has been achieved, such as an early brain structure (cerebral organoids), bone, optic vesicle-like structures (eye), cardiac muscle tissue (heart), primitive pancreas islet cells, a tooth-like structure (teeth), and functional liver buds (liver). Thus, iPSC technology offers, in the future, the powerful and unique possibility to make body organs for transplantation removing the need for organ donation and immune suppressing drugs. Whilst it is clear that iPSCs are rapidly becoming the lead cell type for research into cell replacement therapy and body organ transplantation strategies in humans, it is not known whether (1) such transplants will stimulate host immune responses; and (2) whether this technology will be capable of the bioengineering of a complete and fully functional human organ. This review will not focus on reprogramming to iPSCs, of which a plethora of reviews can be found, but instead focus on the latest developments in direct reprogramming of cells, the bioengineering of body organs from iPSCs, and an analysis of the immune response induced by iPSC-derived cells and tissues. Full article
(This article belongs to the Special Issue Frontiers in Stem Cell Treatments)
Open AccessReview Towards a Treatment of Stress Urinary Incontinence: Application of Mesenchymal Stromal Cells for Regeneration of the Sphincter Muscle
J. Clin. Med. 2014, 3(1), 197-215; doi:10.3390/jcm3010197
Received: 13 December 2013 / Revised: 16 January 2014 / Accepted: 17 January 2014 / Published: 24 February 2014
Cited by 4 | PDF Full-text (2030 KB) | HTML Full-text | XML Full-text
Abstract
Stress urinary incontinence is a significant social, medical, and economic problem. It is caused, at least in part, by degeneration of the sphincter muscle controlling the tightness of the urinary bladder. This muscular degeneration is characterized by a loss of muscle cells [...] Read more.
Stress urinary incontinence is a significant social, medical, and economic problem. It is caused, at least in part, by degeneration of the sphincter muscle controlling the tightness of the urinary bladder. This muscular degeneration is characterized by a loss of muscle cells and a surplus of a fibrous connective tissue. In Western countries approximately 15% of all females and 10% of males are affected. The incidence is significantly higher among senior citizens, and more than 25% of the elderly suffer from incontinence. When other therapies, such as physical exercise, pharmacological intervention, or electrophysiological stimulation of the sphincter fail to improve the patient’s conditions, a cell-based therapy may improve the function of the sphincter muscle. Here, we briefly summarize current knowledge on stem cells suitable for therapy of urinary incontinence: mesenchymal stromal cells, urine-derived stem cells, and muscle-derived satellite cells. In addition, we report on ways to improve techniques for surgical navigation, injection of cells in the sphincter muscle, sensors for evaluation of post-treatment therapeutic outcome, and perspectives derived from recent pre-clinical studies. Full article
(This article belongs to the Special Issue Frontiers in Stem Cell Treatments)
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Open AccessReview Adult Stem Cells and Diseases of Aging
J. Clin. Med. 2014, 3(1), 88-134; doi:10.3390/jcm3010088
Received: 20 November 2013 / Revised: 15 December 2013 / Accepted: 17 December 2013 / Published: 21 January 2014
Cited by 15 | PDF Full-text (616 KB) | HTML Full-text | XML Full-text
Abstract
Preservation of adult stem cells pools is critical for maintaining tissue homeostasis into old age. Exhaustion of adult stem cell pools as a result of deranged metabolic signaling, premature senescence as a response to oncogenic insults to the somatic genome, and other [...] Read more.
Preservation of adult stem cells pools is critical for maintaining tissue homeostasis into old age. Exhaustion of adult stem cell pools as a result of deranged metabolic signaling, premature senescence as a response to oncogenic insults to the somatic genome, and other causes contribute to tissue degeneration with age. Both progeria, an extreme example of early-onset aging, and heritable longevity have provided avenues to study regulation of the aging program and its impact on adult stem cell compartments. In this review, we discuss recent findings concerning the effects of aging on stem cells, contributions of stem cells to age-related pathologies, examples of signaling pathways at work in these processes, and lessons about cellular aging gleaned from the development and refinement of cellular reprogramming technologies. We highlight emerging therapeutic approaches to manipulation of key signaling pathways corrupting or exhausting adult stem cells, as well as other approaches targeted at maintaining robust stem cell pools to extend not only lifespan but healthspan. Full article
(This article belongs to the Special Issue Frontiers in Stem Cell Treatments)
Open AccessReview Stem Cells on Biomaterials for Synthetic Grafts to Promote Vascular Healing
J. Clin. Med. 2014, 3(1), 39-87; doi:10.3390/jcm3010039
Received: 6 October 2013 / Revised: 28 October 2013 / Accepted: 16 November 2013 / Published: 15 January 2014
Cited by 2 | PDF Full-text (877 KB) | HTML Full-text | XML Full-text
Abstract
This review is divided into two interconnected parts, namely a biological and a chemical one. The focus of the first part is on the biological background for constructing tissue-engineered vascular grafts to promote vascular healing. Various cell types, such as embryonic, mesenchymal [...] Read more.
This review is divided into two interconnected parts, namely a biological and a chemical one. The focus of the first part is on the biological background for constructing tissue-engineered vascular grafts to promote vascular healing. Various cell types, such as embryonic, mesenchymal and induced pluripotent stem cells, progenitor cells and endothelial- and smooth muscle cells will be discussed with respect to their specific markers. The in vitro and in vivo models and their potential to treat vascular diseases are also introduced. The chemical part focuses on strategies using either artificial or natural polymers for scaffold fabrication, including decellularized cardiovascular tissue. An overview will be given on scaffold fabrication including conventional methods and nanotechnologies. Special attention is given to 3D network formation via different chemical and physical cross-linking methods. In particular, electron beam treatment is introduced as a method to combine 3D network formation and surface modification. The review includes recently published scientific data and patents which have been registered within the last decade. Full article
(This article belongs to the Special Issue Frontiers in Stem Cell Treatments)
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Open AccessReview The Regenerative Role of the Fetal and Adult Stem Cell Secretome
J. Clin. Med. 2013, 2(4), 302-327; doi:10.3390/jcm2040302
Received: 9 October 2013 / Revised: 17 November 2013 / Accepted: 25 November 2013 / Published: 17 December 2013
Cited by 3 | PDF Full-text (382 KB) | HTML Full-text | XML Full-text
Abstract
For a long time, the stem cell regenerative paradigm has been based on the assumption that progenitor cells play a critical role in tissue repair by means of their plasticity and differentiation potential. However, recent works suggest that the mechanism underlying the [...] Read more.
For a long time, the stem cell regenerative paradigm has been based on the assumption that progenitor cells play a critical role in tissue repair by means of their plasticity and differentiation potential. However, recent works suggest that the mechanism underlying the benefits of stem cell transplantation might relate to a paracrine modulatory effect rather than the replacement of affected cells at the site of injury. Therefore, mounting evidence that stem cells may act as a reservoir of trophic signals released to modulate the surrounding tissue has led to a paradigm shift in regenerative medicine. Attention has been shifted from analysis of the stem cell genome to understanding the stem cell “secretome”, which is represented by the growth factors, cytokines and chemokines produced through paracrine secretion. Insights into paracrine-mediated repair support a new approach in regenerative medicine and the isolation and administration of specific stem cell-derived paracrine factors may represent an extremely promising strategy, introducing paracrine-based therapy as a novel and feasible clinical application. In this review, we will discuss the regenerative potential of fetal and adult stem cells, with particular attention to their secretome. Full article
(This article belongs to the Special Issue Frontiers in Stem Cell Treatments)
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Open AccessReview An Update on Translating Stem Cell Therapy for Stroke from Bench to Bedside
J. Clin. Med. 2013, 2(4), 220-241; doi:10.3390/jcm2040220
Received: 29 August 2013 / Revised: 16 September 2013 / Accepted: 21 September 2013 / Published: 1 November 2013
Cited by 2 | PDF Full-text (351 KB) | HTML Full-text | XML Full-text
Abstract
With a constellation of stem cell sources available, researchers hope to utilize their potential for cellular repair as a therapeutic target for disease. However, many lab-to-clinic translational considerations must be given in determining their efficacy, variables such as the host response, effects [...] Read more.
With a constellation of stem cell sources available, researchers hope to utilize their potential for cellular repair as a therapeutic target for disease. However, many lab-to-clinic translational considerations must be given in determining their efficacy, variables such as the host response, effects on native tissue, and potential for generating tumors. This review will discuss the current knowledge of stem cell research in neurological disease, mainly stroke, with a focus on the benefits, limitations, and clinical potential. Full article
(This article belongs to the Special Issue Frontiers in Stem Cell Treatments)
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Open AccessReview Mesenchymal Stromal Cells: Updates and Therapeutic Outlook in Rheumatic Diseases
J. Clin. Med. 2013, 2(4), 201-213; doi:10.3390/jcm2040201
Received: 16 August 2013 / Revised: 10 September 2013 / Accepted: 27 September 2013 / Published: 23 October 2013
PDF Full-text (441 KB) | HTML Full-text | XML Full-text
Abstract
Multipotent mesenchymal stromal cells or mesenchymal stem cells (MSCs) are adult stem cells exhibiting functional properties that have opened the way for cell-based clinical therapies. MSCs have been reported to exhibit immunosuppressive as well as healing properties, improving angiogenesis and preventing apoptosis [...] Read more.
Multipotent mesenchymal stromal cells or mesenchymal stem cells (MSCs) are adult stem cells exhibiting functional properties that have opened the way for cell-based clinical therapies. MSCs have been reported to exhibit immunosuppressive as well as healing properties, improving angiogenesis and preventing apoptosis or fibrosis through the secretion of paracrine mediators. This review summarizes recent progress on the clinical application of stem cells therapy in some inflammatory and degenerative rheumatic diseases. To date, most of the available data have been obtained in preclinical models and clinical efficacy needs to be evaluated through controlled randomized double-blind trials. Full article
(This article belongs to the Special Issue Frontiers in Stem Cell Treatments)
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