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      In vitro expansion impaired the stemness of early passage mesenchymal stem cells for treatment of cartilage defects

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          Abstract

          In vitro cultured autologous mesenchymal stem cells (MSCs) within passage 5 have been approved for clinical application in stem cell-based treatment of cartilage defects. However, their chondrogenic potential has not yet been questioned or verified. In this study, the chondrogenic potential of bone marrow MSCs at passage 3 (P3 BMSCs) was investigated both in cartilage repair and in vitro, with freshly isolated bone marrow mononuclear cells (BMMNCs) as controls. The results showed that P3 BMSCs were inferior to BMMNCs not only in their chondrogenic differentiation ability but also as candidates for long-term repair of cartilage defects. Compared with BMMNCs, P3 BMSCs presented a decay in telomerase activity and a change in chromosomal morphology with potential anomalous karyotypes, indicating senescence. In addition, interindividual variability in P3 BMSCs is much higher than in BMMNCs, demonstrating genomic instability. Interestingly, remarkable downregulation in cell cycle, DNA replication and mismatch repair (MMR) pathways as well as in multiple genes associated with telomerase activity and chromosomal stability were found in P3 BMSCs. This result indicates that telomerase and chromosome anomalies might originate from expansion, leading to impaired stemness and pluripotency of stem cells. In vitro culture and expansion are not recommended for cell-based therapy, and fresh BMMNCs are the first choice.

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          Mechanisms and functions of DNA mismatch repair.

          Guo-Min Li (2008)
          DNA mismatch repair (MMR) is a highly conserved biological pathway that plays a key role in maintaining genomic stability. The specificity of MMR is primarily for base-base mismatches and insertion/deletion mispairs generated during DNA replication and recombination. MMR also suppresses homeologous recombination and was recently shown to play a role in DNA damage signaling in eukaryotic cells. Escherichia coli MutS and MutL and their eukaryotic homologs, MutSalpha and MutLalpha, respectively, are key players in MMR-associated genome maintenance. Many other protein components that participate in various DNA metabolic pathways, such as PCNA and RPA, are also essential for MMR. Defects in MMR are associated with genome-wide instability, predisposition to certain types of cancer including hereditary non-polyposis colorectal cancer, resistance to certain chemotherapeutic agents, and abnormalities in meiosis and sterility in mammalian systems.
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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.

            Edwin M Horwitz, Patricia L Gordon, Winston 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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              Autologous bone marrow-derived mesenchymal stem cells versus autologous chondrocyte implantation: an observational cohort study.

              E. Feng, Bee Tai, James H P Hui … (2010)
              First-generation autologous chondrocyte implantation has limitations, and introducing new effective cell sources can improve cartilage repair. This study was conducted to compare the clinical outcomes of patients treated with first-generation autologous chondrocyte implantation to patients treated with autologous bone marrow-derived mesenchymal stem cells (BMSCs). Cohort study; Level of evidence, 3. Seventy-two matched (lesion site and age) patients underwent cartilage repair using chondrocytes (n = 36) or BMSCs (n = 36). Clinical outcomes were measured before operation and 3, 6, 9, 12, 18, and 24 months after operation using the International Cartilage Repair Society (ICRS) Cartilage Injury Evaluation Package, which included questions from the Short-Form Health Survey, International Knee Documentation Committee (IKDC) subjective knee evaluation form, Lysholm knee scale, and Tegner activity level scale. There was significant improvement in the patients' quality of life (physical and mental components of the Short Form-36 questionnaire included in the ICRS package) after cartilage repair in both groups (autologous chondrocyte implantation and BMSCs). However, there was no difference between the BMSC and the autologous chondrocyte implantation group in terms of clinical outcomes except for Physical Role Functioning, with a greater improvement over time in the BMSC group (P = .044 for interaction effect). The IKDC subjective knee evaluation (P = .861), Lysholm (P = .627), and Tegner (P = .200) scores did not show any significant difference between groups over time. However, in general, men showed significantly better improvements than women. Patients younger than 45 years of age scored significantly better than patients older than 45 years in the autologous chondrocyte implantation group, but age did not make a difference in outcomes in the BMSC group. Using BMSCs in cartilage repair is as effective as chondrocytes for articular cartilage repair. In addition, it required 1 less knee surgery, reduced costs, and minimized donor-site morbidity.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cell Death Dis
                Journal ID (iso-abbrev): Cell Death Dis
                Title: Cell Death & Disease
                Publisher: Nature Publishing Group
                ISSN (Electronic): 2041-4889
                Publication date (Print): June 2017
                Publication date (Electronic): 01 June 2017
                Publication date PMC-release: 1 June 2017
                Volume: 8
                Issue: 6
                Page: e2851
                Affiliations
                [1 ]Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration, The First Affiliated Hospital of Guangxi Medical University , Nanning 530021, China
                [2 ]Department of Orthopaedics Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University , Nanning 530021, China
                [3 ]Center for Genomic and Personalized Medicine, Guangxi Medical University , Nanning 530021, China
                [4 ]School of Nursing, Guangxi Medical University , Nanning 530021, China
                [5 ]Collaborative Innovation Center of Guangxi Biological Medicine, The First Affiliated Hospital of Guangxi Medical University , Nanning 530021, China
                [6 ]Guangxi Key Laboratory of Regenerative Medicine, The First Affiliated Hospital of Guangxi Medical University , Nanning 530021, China
                [7 ]National Engineering Research Center for Biomaterials, Sichuan University , Chengdu 610064, China
                Author notes
                [* ]Guangxi Engineering Center in Biomedical Material for Tissue and Organ Regeneration, The First Affiliated Hospital of Guangxi Medical University , Shuangyong Road No. 22, Nanning 530021, China. Tel: +86 771 535 8132 or +86 771 535 0189; Fax: +86 771 535 0975 or +86 771 535 0189; E-mail: zhengli224@ 123456163.com or zhaojinmin@ 123456126.com
                [8]

                These authors contributed equally to this work.

                Article
                Publisher Item ID: cddis2017215
                DOI: 10.1038/cddis.2017.215
                PMC ID: 5520885
                PubMed ID: 28569773
                SO-VID: c166c965-1abf-4e97-9a4a-482924fe6de3
                Copyright © Copyright © 2017 The Author(s)
                License:

                Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                Date received : 23 December 2016
                Date revision received : 07 April 2017
                Date accepted : 10 April 2017
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Cell biology
                Data availability:
                ScienceOpen disciplines: Cell biology

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