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Advances in Cell Transplantation 2019

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 June 2019) | Viewed by 26907

Special Issue Editor

Department of Women's and Children's Health, University of Padova, Via Giustiniani, 3, 35128 Padova, Italy
Interests: cell transplantation; cell therapy; paracrine signaling; extracellular vesicles; mesenchymal stem cell immune modulation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cell Transplantation has emerged as a promising field, based on progress in cell and molecular biology, allowing isolation, characterization, expansion, and engineering of cells as potential therapeutic tools. Experience in the last two decades has yielded significant results in the reconstruction of epithelial tissues, such as the skin or the cornea. However, the use of cells for regeneration of more complex organs, such as the heart or the brain, has met more difficulties, probably due to limited knowledge on the mechanisms underlying cell grafting and integration into host tissues. In other words, as predicted by Neil Theise twenty years ago, knowledge of tissue biology did not parallel progress in cell and molecular biology. The concept of “replacing” diseased or aged organs with younger and more active cells, such as stem cells, has dominated the field for some years. Experimental and clinical evidence now indicates that repopulation of non-epithelial tissues with exogenous cells is generally inconsistent, supporting an indirect primary mechanism other than structural integration of transplanted cells at the injured site, and it is generally accepted that such underlying mechanisms can be mostly characterized as paracrine effects.

Despite these limitations, with the resulting failures, wave of disillusionment and reduced investments in the first decade of the 2000s, the field of Cell Transplantation is now entering a new phase of growth, propelled by better understanding of the therapeutic mechanisms of action, novel applications in oncology as well as by upgraded technology for cell isolation, expansion and delivery under GMP conditions. Recent advances in gene therapy also open the fascinating possibility to cure genetic diseases by cell replacement with genetically corrected autologous precursor cells.

Such renewed confidence is also testified by the entry of Big Pharma in the field. Critical hurdles still include accurate selection of target indications, predictive markers of response to treatment and economic sustainability. Since Cell Transplantation is often directed to highly selected populations of patients afferent to specialized Clinics, it is mandatory to shape a model of personalized medicine where Industry and Hospitals work in close cooperation.

Following the success of the previous issue dedicated to Cell Transplantation, this Special Issue will cover the whole pathway, translating scientific advances into therapeutic interventions, including in vitro and in vivo studies on mechanisms of action, animal models of target diseases, GMP production, and clinical trials. Manuscripts covering the links between cell therapy and gene therapy are particularly welcome. Original research papers, full reviews and commentaries are all welcome.

Assoc. Prof. Dr. Maurizio Muraca
Guest Editor

Manuscript Submission Information

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. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short 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 thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • animal models
  • bioreactors
  • cell engineering
  • cell factory
  • cell immunotherapy
  • cell transplantation
  • clinical trials
  • embryonic stem cells
  • gene therapy
  • gmp facility
  • induced pluripotent stem cells
  • mesenchymal stem/stromal cells
  • paracrine signaling
  • somatic stem cells

Related Special Issue

Published Papers (6 papers)

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Research

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19 pages, 4157 KiB  
Article
Enhanced Homing of Mesenchymal Stem Cells Overexpressing Fibroblast Growth Factor 21 to Injury Site in a Mouse Model of Traumatic Brain Injury
by Rami Ahmad Shahror, Ahmed Atef Ahmed Ali, Chung-Che Wu, Yung-Hsiao Chiang and Kai-Yun Chen
Int. J. Mol. Sci. 2019, 20(11), 2624; https://doi.org/10.3390/ijms20112624 - 28 May 2019
Cited by 27 | Viewed by 4303
Abstract
Mesenchymal stem cells (MSCs) are emerging as a potential therapeutic intervention for brain injury due to their neuroprotective effects and safe profile. However, the homing ability of MSCs to injury sites still needs to be improved. Fibroblast Growth Factor 21 (FGF21) was recently [...] Read more.
Mesenchymal stem cells (MSCs) are emerging as a potential therapeutic intervention for brain injury due to their neuroprotective effects and safe profile. However, the homing ability of MSCs to injury sites still needs to be improved. Fibroblast Growth Factor 21 (FGF21) was recently reported to enhance cells migration in different cells type. In this study, we investigated whether MSCs that overexpressing FGF21 (MSC-FGF21) could exhibit enhanced homing efficacy in brain injury. We used novel Molday IONEverGreen™ (MIEG) as cell labeling probe that enables a non-invasive, high-sensitive and real-time MRI tracking. Using a mouse model of traumatic brain injury (TBI), MIEG labeled MSCs were transplanted into the contralateral lateral ventricle followed by real-time MRI tracking. FGF21 retained MSC abilities of proliferation and morphology. MSC-FGF21 showed significantly greater migration in transwell assay compared to control MSC. MIEG labeling showed no effects on MSCs’ viability, proliferation and differentiation. Magnetic resonance imaging (MRI) revealed that FGF21 significantly enhances the homing of MSC toward injury site. Histological analysis further confirmed the MRI findings. Taken together, these results show that FGF21 overexpression and MIEG labeling of MSC enhances their homing abilities and enables non-invasive real time tracking of the transplanted cells, provides a promising approach for MSC based therapy and tracking in TBI. Full article
(This article belongs to the Special Issue Advances in Cell Transplantation 2019)
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12 pages, 1820 KiB  
Article
Individual Immune-Modulatory Capabilities of MSC-Derived Extracellular Vesicle (EV) Preparations and Recipient-Dependent Responsiveness
by Lambros Kordelas, Esther Schwich, Robin Dittrich, Peter A. Horn, Dietrich W. Beelen, Verena Börger, Bernd Giebel and Vera Rebmann
Int. J. Mol. Sci. 2019, 20(7), 1642; https://doi.org/10.3390/ijms20071642 - 02 Apr 2019
Cited by 31 | Viewed by 3923
Abstract
Treatment with extracellular vesicles (EVs) derived from mesenchymal stem/stromal cells (MSCs) have been suggested as novel therapeutic option in acute inflammation-associated disorders due to their immune-modulatory capacities. As we have previously observed differences in the cytokine profile of independent MSC-EV preparations, functional differences [...] Read more.
Treatment with extracellular vesicles (EVs) derived from mesenchymal stem/stromal cells (MSCs) have been suggested as novel therapeutic option in acute inflammation-associated disorders due to their immune-modulatory capacities. As we have previously observed differences in the cytokine profile of independent MSC-EV preparations, functional differences of MSC-EV preparations have to be considered. To evaluate the immune-modulatory capabilities of specific MSC-EV preparations, reliable assays are required to characterize the functionality of MSC-EV preparations prior to administration to a patient. To this end, we established an in vitro assay evaluating the immune-modulatory capacities of MSC-EV preparations. Here, we compared the efficacy of four independent MSC-EV preparations to modulate the induction of T cell differentiation and cytokine production after phorbol 12-myristate 13-acetate (PMA)/Ionomycin stimulation of peripheral blood mononuclear cells (PBMC) derived from six healthy donors. Flow cytometric analyses revealed that the four MSC-EV preparations differentially modulate the expression of surface markers, such as CD45RA, on CD4+ and CD8+ T cells, resulting in shifts in the frequencies of effector and effector memory T cells. Moreover, cytokine profile in T cell subsets was affected in a MSC-EV-specific manner exclusively in CD8+ naïve T cells. Strikingly, hierarchical clustering revealed that the T cell response towards the MSC-EV preparations largely varied among the different PBMC donors. Thus, besides defining functional activity of MSC-EV preparations, it will be crucial to test whether patients intended for treatment with MSC-EV preparations are in principal competent to respond to the envisioned MSC-EV therapy. Full article
(This article belongs to the Special Issue Advances in Cell Transplantation 2019)
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16 pages, 1616 KiB  
Communication
Immunological Heterogeneity of Healthy Peripheral Blood Stem Cell Donors—Effects of Granulocyte Colony-Stimulating Factor on Inflammatory Responses
by Tor Henrik Anderson Tvedt, Guro K. Melve, Galina Tsykunova, Aymen Bushra Ahmed, Annette K. Brenner and Øystein Bruserud
Int. J. Mol. Sci. 2018, 19(10), 2886; https://doi.org/10.3390/ijms19102886 - 22 Sep 2018
Cited by 8 | Viewed by 3114
Abstract
Interleukin-6 (IL-6) contributes to the development of immune-mediated complications after allogeneic stem cell transplantation. However, systemic IL-6 levels also increase during granulocyte colony-stimulating factor (G-CSF) mobilization of hematopoietic stem cells in healthy donors, but it is not known whether this mobilization alters systemic [...] Read more.
Interleukin-6 (IL-6) contributes to the development of immune-mediated complications after allogeneic stem cell transplantation. However, systemic IL-6 levels also increase during granulocyte colony-stimulating factor (G-CSF) mobilization of hematopoietic stem cells in healthy donors, but it is not known whether this mobilization alters systemic levels of other IL-6 family cytokines/receptors and whether such effects differ between donors. We examined how G-CSF administration influenced C-reactive protein (CRP) levels (85 donors) and serum levels of IL-6 family cytokines/receptors (20 donors). G-CSF increased CRP levels especially in elderly donors with high pretherapy levels, but these preharvesting levels did not influence clinical outcomes (nonrelapse mortality, graft versus host disease). The increased IL-6 levels during G-CSF therapy normalized within 24 h after treatment. G-CSF administration did not alter serum levels of other IL-6-familly mediators. Oncostatin M, but not IL-6, showed a significant correlation with CRP levels during G-CSF therapy. Clustering analysis of mediator levels during G-CSF administration identified two donor subsets mainly characterized by high oncostatin M and IL-6 levels, respectively. Finally, G-CSF could increase IL-6 release by in vitro cultured monocytes, fibroblasts, and mesenchymal stem cells. In summary, G-CSF seems to induce an acute phase reaction with increased systemic IL-6 levels in healthy stem cell donors. Full article
(This article belongs to the Special Issue Advances in Cell Transplantation 2019)
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Review

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15 pages, 928 KiB  
Review
Unveiling Mesenchymal Stromal Cells’ Organizing Function in Regeneration
by Peter P. Nimiritsky, Roman Yu. Eremichev, Natalya A. Alexandrushkina, Anastasia Yu. Efimenko, Vsevolod A. Tkachuk and Pavel I. Makarevich
Int. J. Mol. Sci. 2019, 20(4), 823; https://doi.org/10.3390/ijms20040823 - 14 Feb 2019
Cited by 26 | Viewed by 6235
Abstract
Regeneration is a fundamental process attributed to the functions of adult stem cells. In the last decades, delivery of suspended adult stem cells is widely adopted in regenerative medicine as a leading means of cell therapy. However, adult stem cells cannot complete the [...] Read more.
Regeneration is a fundamental process attributed to the functions of adult stem cells. In the last decades, delivery of suspended adult stem cells is widely adopted in regenerative medicine as a leading means of cell therapy. However, adult stem cells cannot complete the task of human body regeneration effectively by themselves as far as they need a receptive microenvironment (the niche) to engraft and perform properly. Understanding the mechanisms underlying mammalian regeneration leads us to an assumption that improved outcomes of cell therapy require a specific microenvironment that is generated in damaged areas prior to stem cell delivery. To a certain extent, it may be achieved by the delivery of mesenchymal stromal cells (MSCs), not in dispersed form, but rather in self-organized cell sheets (CS) – tissue-like structures comprised of viable cells and microenvironment components: extracellular matrix and soluble factors deposited in the matrix. In this review, we highlight the potential role of MSCs as regeneration organizers and speculate that this function emerges in CS. This concept shifts our understanding of the therapeutic mechanism underlying a widely known CS-based delivery method for regenerative medicine. Full article
(This article belongs to the Special Issue Advances in Cell Transplantation 2019)
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16 pages, 1131 KiB  
Review
Mechanisms Underlying the Visual Benefit of Cell Transplantation for the Treatment of Retinal Degenerations
by Thierry Léveillard and Laurence Klipfel
Int. J. Mol. Sci. 2019, 20(3), 557; https://doi.org/10.3390/ijms20030557 - 28 Jan 2019
Cited by 7 | Viewed by 3979
Abstract
The transplantation of retinal cells has been studied in animals to establish proof of its potential benefit for the treatment of blinding diseases. Photoreceptor precursors have been grafted in animal models of Mendelian-inherited retinal degenerations, and retinal pigmented epithelial cells have been used [...] Read more.
The transplantation of retinal cells has been studied in animals to establish proof of its potential benefit for the treatment of blinding diseases. Photoreceptor precursors have been grafted in animal models of Mendelian-inherited retinal degenerations, and retinal pigmented epithelial cells have been used to restore visual function in animal models of age-related macular degeneration (AMD) and recently in patients. Cell therapy over corrective gene therapy in inherited retinal degeneration can overcome the genetic heterogeneity by providing one treatment for all genetic forms of the diseases. In AMD, the existence of multiple risk alleles precludes a priori the use of corrective gene therapy. Mechanistically, the experiments of photoreceptor precursor transplantation reveal the importance of cytoplasmic material exchange between the grafted cells and the host cells for functional rescue, an unsuspected mechanism and novel concept. For transplantation of retinal pigmented epithelial cells, the mechanisms behind the therapeutic benefit are only partially understood, and clinical trials are ongoing. The fascinating studies that describe the development of methodologies to produce cells to be grafted and demonstrate the functional benefit for vision are reviewed. Full article
(This article belongs to the Special Issue Advances in Cell Transplantation 2019)
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23 pages, 791 KiB  
Review
Mesenchymal Stem Cell Expressing TRAIL as Targeted Therapy against Sensitised Tumour
by Kamal Shaik Fakiruddin, Nadiah Ghazalli, Moon Nian Lim, Zubaidah Zakaria and Syahril Abdullah
Int. J. Mol. Sci. 2018, 19(8), 2188; https://doi.org/10.3390/ijms19082188 - 27 Jul 2018
Cited by 22 | Viewed by 4905
Abstract
Tapping into the ability of engineered mesenchymal stem cells (MSCs) to mobilise into the tumour has expanded the scope of cancer treatment. Engineered MSCs expressing tumour necrosis factor (TNF)-related apoptosis inducing ligand (MSC-TRAIL) could serve as a platform for an efficient and targeted [...] Read more.
Tapping into the ability of engineered mesenchymal stem cells (MSCs) to mobilise into the tumour has expanded the scope of cancer treatment. Engineered MSCs expressing tumour necrosis factor (TNF)-related apoptosis inducing ligand (MSC-TRAIL) could serve as a platform for an efficient and targeted form of therapy. However, the presence of cancer stem cells (CSCs) that are resistant to TRAIL and apoptosis may represent a challenge for effective treatment. Nonetheless, with the discovery of small molecular inhibitors that could target CSCs and tumour signalling pathways, a higher efficacy of MSC-TRAIL mediated tumour inhibition can be achieved. This might pave the way for a more effective form of combined therapy, which leads to a better treatment outcome. In this review, we first discuss the tumour-homing capacity of MSCs, its effect in tumour tropism, the different approach behind genetically-engineered MSCs, and the efficacy and safety of each agent delivered by these MSCs. Then, we focus on how sensitisation of CSCs and tumours using small molecular inhibitors can increase the effect of these cells to either TRAIL or MSC-TRAIL mediated inhibition. In the conclusion, we address a few questions and safety concerns regarding the utilization of engineered MSCs for future treatment in patients. Full article
(This article belongs to the Special Issue Advances in Cell Transplantation 2019)
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