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      Challenges in Clinical Development of Mesenchymal Stromal/Stem Cells: Concise Review

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          Identified 50 years ago, mesenchymal stromal/stem cells (MSCs) immediately generated a substantial interest among the scientific community because of their differentiation plasticity and hematopoietic supportive function. Early investigations provided evidence of a relatively low engraftment rate and a transient benefit for challenging congenital and acquired diseases. The reasons for these poor therapeutic benefits forced the entire field to reconsider MSC mechanisms of action together with their ex vivo manipulation procedures. This phase resulted in advances in MSCs processing and the hypothesis that MSC‐tissue supportive functions may be prevailing their differentiation plasticity, broadening the spectrum of MSCs therapeutic potential far beyond their lineage‐restricted commitments. Consequently, an increasing number of studies have been conducted for a variety of clinical indications, revealing additional challenges and suggesting that MSCs are still lagging behind for a solid clinical translation. For this reason, our aim was to dissect the current challenges in the development of still promising cell types that, after more than half a century, still need to reach their maturity. stem cells translational medicine 2019;8:1135–1148

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          Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair--current views.

          Donald G. Phinney, Darwin J. Prockop (2007)
          Mesenchymal stem cells or multipotent stromal cells (MSCs) isolated from the bone marrow of adult organisms were initially characterized as plastic adherent, fibroblastoid cells with the capacity to generate heterotopic osseous tissue when transplanted in vivo. In recent years, MSCs or MSC-like cells have been shown to reside within the connective tissue of most organs, and their surface phenotype has been well described. A large number of reports have also indicated that the cells possess the capacity to transdifferentiate into epithelial cells and lineages derived from the neuroectoderm. The broad developmental plasticity of MSCs was originally thought to contribute to their demonstrated efficacy in a wide variety of experimental animal models of disease as well as in human clinical trials. However, new findings suggest that the ability of MSCs to alter the tissue microenvironment via secretion of soluble factors may contribute more significantly than their capacity for transdifferentiation in tissue repair. Herein, we critically evaluate the literature describing the plasticity of MSCs and offer insight into how the molecular and functional heterogeneity of this cell population, which reflects the complexity of marrow stroma as an organ system, may confound interpretation of their transdifferentiation potential. Additionally, we argue that this heterogeneity also provides a basis for the broad therapeutic efficacy of MSCs.
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            Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone.

            E Horwitz, P L Gordon, W. K. K. Koo … (2002)
            Treatment with isolated allogeneic mesenchymal cells has the potential to enhance the therapeutic effects of conventional bone marrow transplantation in patients with genetic disorders affecting mesenchymal tissues, including bone, cartilage, and muscle. To demonstrate the feasibility of mesenchymal cell therapy and to gain insight into the transplant biology of these cells, we used gene-marked, donor marrow-derived mesenchymal cells to treat six children who had undergone standard bone marrow transplantation for severe osteogenesis imperfecta. Each child received two infusions of the allogeneic cells. Five of six patients showed engraftment in one or more sites, including bone, skin, and marrow stroma, and had an acceleration of growth velocity during the first 6 mo postinfusion. This improvement ranged from 60% to 94% (median, 70%) of the predicted median values for age- and sex-matched unaffected children, compared with 0% to 40% (median, 20%) over the 6 mo immediately preceding the infusions. There was no clinically significant toxicity except for an urticarial rash in one patient just after the second infusion. Failure to detect engraftment of cells expressing the neomycin phosphotransferase marker gene suggested the potential for immune attack against therapeutic cells expressing a foreign protein. Thus, allogeneic mesenchymal cells offer feasible posttransplantation therapy for osteogenesis imperfecta and likely other disorders originating in mesenchymal precursors.
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              Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis.

              Dimitrios Karussis, Clementine Karageorgiou, Adi Vaknin-Dembinsky … (2010)
              To evaluate the feasibility, safety, and immunological effects of intrathecal and intravenous administration of autologous mesenchymal stem cells (MSCs) (also called mesenchymal stromal cells) in patients with multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). A phase 1/2 open-safety clinical trial. Patients  Fifteen patients with MS (mean [SD] Expanded Disability Status Scale [EDSS] score, 6.7 [1.0]) and 19 with ALS (mean [SD] Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS] score, 20.8 [8.0]) were enrolled. Intervention  After culture, a mean (SD) of 63.2 × 10(6) (2.5 × 10(6)) MSCs was injected intrathecally (n = 34) and intravenously (n = 14). In 9 cases, MSCs were magnetically labeled with the superparamagnetic iron oxide ferumoxides (Feridex). The main outcome measure was the recording of side effects. Follow-up (≤25 months) included adverse events evaluation, neurological disability assessment by means of the EDSS, magnetic resonance imaging to exclude unexpected pathologies and track the labeled stem cells, and immunological tests to assess the short-term immunomodulatory effects of MSC transplantation. Twenty-one patients had injection-related adverse effects consisting of transient fever, and 15 reported headache. No major adverse effects were reported during follow-up. The mean ALSFRS score remained stable during the first 6 months of observation, whereas the mean (SD) EDSS score improved from 6.7 (1.0) to 5.9 (1.6). Magnetic resonance imaging visualized the MSCs in the occipital horns of the ventricles, indicating the possible migration of ferumoxides-labeled cells in the meninges, subarachnoid space, and spinal cord. Immunological analysis revealed an increase in the proportion of CD4(+)CD25(+) regulatory T cells, a decrease in the proliferative responses of lymphocytes, and the expression of CD40(+), CD83(+), CD86(+), and HLA-DR on myeloid dendritic cells at 24 hours after MSC transplantation. Transplantation of MSCs in patients with MS and ALS is a clinically feasible and relatively safe procedure and induces immediate immunomodulatory effects. Trial Registration  clinicaltrials.gov Identifier: NCT00781872.
              Article 0 comments Cited 283 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Massimo Dominici:
                ORCID: https://orcid.org/0000-0002-4007-1503
                massimo.dominici@unimore.it
                Journal
                Journal ID (nlm-ta): Stem Cells Transl Med
                Journal ID (iso-abbrev): Stem Cells Transl Med
                Journal ID (doi): 10.1002/(ISSN)2157-6580
                Journal ID (publisher-id): SCT3
                Title: Stem Cells Translational Medicine
                Publisher: John Wiley & Sons, Inc. (Hoboken, USA )
                ISSN (Print): 2157-6564
                ISSN (Electronic): 2157-6580
                Publication date (Electronic): 16 July 2019
                Publication date Collection: November 2019
                Volume: 8
                Issue: 11 ( doiID: 10.1002/sct3.v8.11 )
                Pages: 1135-1148
                Affiliations
                [ 1 ] Laboratory of Cellular Therapy, Program of Cell Therapy and Immuno‐Oncology, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults University‐Hospital of Modena and Reggio Emilia Modena Italy
                [ 2 ] Aflac Cancer and Blood Disorders Center Children's Healthcare of Atlanta and Emory University Department of Pediatrics Atlanta Georgia USA
                [ 3 ] Rigenerand srl Medolla Modena Italy
                [ 4 ] Technopole of Mirandola TPM Mirandola Modena Italy
                Author notes
                [*] [* ]Correspondence: Massimo Dominici, M.D., Laboratory of Cellular Therapy, University of Modena & Reggio Emilia, Via Del Pozzo, 71, Modena, Italy. Telephone: 390594222858; e‐mail: massimo.dominici@ 123456unimore.it
                Author information
                https://orcid.org/0000-0002-4007-1503
                Article
                Publisher ID: SCT312544
                DOI: 10.1002/sctm.19-0044
                PMC ID: 6811694
                PubMed ID: 31313507
                SO-VID: a3b34536-edba-4bc1-8fc9-5f8ccaa8aa91
                Copyright © © 2019 The Authors. stem cells translational medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                Date received : 12 February 2019
                Date accepted : 17 June 2019
                Page count
                Figures: 2, Tables: 1, Pages: 14, Words: 16156
                Funding
                Funded by: Ministero Istruzione Università Ricerca (MIUR)
                Award ID: 733288
                Categories
                Subject: Perspectives
                Subject: Perspectives
                Custom metadata
                source-schema-version-number 2.0
                component-id sct312544
                cover-date November 2019
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.7.0 mode:remove_FC converted:24.10.2019

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