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      Cryopreservation does not change the performance and characteristics of allogenic mesenchymal stem cells highly over-expressing a cytoplasmic therapeutic transgene for cancer treatment

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          Abstract

          Background

          Mesenchymal stem cells (MSCs) driven gene directed enzyme prodrug therapy is a promising approach to deliver therapeutic agents to target heterogenous solid tumours. To democratize such a therapy, cryopreservation along with cold chain transportation is an essential part of the logistical process and supply chain. Previously, we have successfully engineered MSCs by a non-viral DNA transfection approach for prolonged and exceptionally high expression of the fused transgene cytosine deaminase, uracil phosphoribosyl transferase and green fluorescent protein (CD::UPRT::GFP). The aim of this study was to determine the effects of cryopreservation of MSCs engineered to highly overexpress this cytoplasmic therapeutic transgene.

          Methods

          Modified MSCs were preserved in a commercially available, GMP-grade cryopreservative—CryoStor10 (CS10) for up to 11 months. Performance of frozen-modified MSCs was compared to freshly modified equivalents in vitro. Cancer killing potency was evaluated using four different cancer cell lines. Migratory potential was assessed using matrigel invasion assay and flow cytometric analysis for CXCR4 expression. Frozen-modified MSC was used to treat canine patients via intra-tumoral injections, or by intravenous infusion followed by a daily dose of 5-flucytosine (5FC).

          Results

          We found that cryopreservation did not affect the transgene expression, cell viability, adhesion, phenotypic profile, and migration of gene modified canine adipose tissue derived MSCs. In the presence of 5FC, the thawed and freshly modified MSCs showed comparable cytotoxicity towards one canine and three human cancer cell lines in vitro. These cryopreserved cells were stored for about a year and then used to treat no-option-left canine patients with two different types of cancers and notably, the patients showed progression-free interval of more than 20 months, evidence of the effectiveness in treating spontaneously occurring cancers.

          Conclusion

          This study supports the use of cryopreserved, off-the-shelf transiently transfected MSCs for cancer treatment.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s13287-022-03198-z.

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          Most cited references68

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          Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.

          M Dominici, K Le Blanc, I. Mueller … (2006)
          The considerable therapeutic potential of human multipotent mesenchymal stromal cells (MSC) has generated markedly increasing interest in a wide variety of biomedical disciplines. However, investigators report studies of MSC using different methods of isolation and expansion, and different approaches to characterizing the cells. Thus it is increasingly difficult to compare and contrast study outcomes, which hinders progress in the field. To begin to address this issue, the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy proposes minimal criteria to define human MSC. First, MSC must be plastic-adherent when maintained in standard culture conditions. Second, MSC must express CD105, CD73 and CD90, and lack expression of CD45, CD34, CD14 or CD11b, CD79alpha or CD19 and HLA-DR surface molecules. Third, MSC must differentiate to osteoblasts, adipocytes and chondroblasts in vitro. While these criteria will probably require modification as new knowledge unfolds, we believe this minimal set of standard criteria will foster a more uniform characterization of MSC and facilitate the exchange of data among investigators.
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            Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma

            Aarif Khakoo, Shibani Pati, Stasia A. Anderson … (2006)
            Emerging evidence suggests that both human stem cells and mature stromal cells can play an important role in the development and growth of human malignancies. In contrast to these tumor-promoting properties, we observed that in an in vivo model of Kaposi's sarcoma (KS), intravenously (i.v.) injected human mesenchymal stem cells (MSCs) home to sites of tumorigenesis and potently inhibit tumor growth. We further show that human MSCs can inhibit the in vitro activation of the Akt protein kinase within some but not all tumor and primary cell lines. The inhibition of Akt activity requires the MSCs to make direct cell–cell contact and can be inhibited by a neutralizing antibody against E-cadherin. We further demonstrate that in vivo, Akt activation within KS cells is potently down-regulated in areas adjacent to MSC infiltration. Finally, the in vivo tumor-suppressive effects of MSCs correlates with their ability to inhibit target cell Akt activity, and KS tumors engineered to express a constitutively activated Akt construct are no longer sensitive to i.v. MSC administration. These results suggest that in contrast to other stem cells or normal stromal cells, MSCs possess intrinsic antineoplastic properties and that this stem cell population might be of particular utility for treating those human malignancies characterized by dysregulated Akt.
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              Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial

              Michael Matthay, Carolyn S Calfee, Hanjing Zhuo … (2019)
              Treatment with bone-marrow-derived mesenchymal stromal cells (MSCs) has shown benefits in preclinical models of acute respiratory distress syndrome (ARDS). Safety has not been established for administration of MSCs in critically ill patients with ARDS. We did a phase 2a trial to assess safety after administration of MSCs to patients with moderate to severe ARDS.
              Article 0 comments Cited 236 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Yoon Khei Ho:
                ORCID: http://orcid.org/0000-0001-5696-1407
                bchhyk@nus.edu.sg
                Journal
                Journal ID (nlm-ta): Stem Cell Res Ther
                Journal ID (iso-abbrev): Stem Cell Res Ther
                Title: Stem Cell Research & Therapy
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1757-6512
                Publication date (Electronic): 14 November 2022
                Publication date PMC-release: 14 November 2022
                Publication date Collection: 2022
                Volume: 13
                Electronic Location Identifier: 519
                Affiliations
                [1 ]GRID grid.4280.e, ISNI 0000 0001 2180 6431, Department of Biochemistry, , National University of Singapore, ; Singapore, 117596 Singapore
                [2 ]GRID grid.4280.e, ISNI 0000 0001 2180 6431, NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, , National University of Singapore, ; Singapore, Singapore
                [3 ]Gentle Oak Veterinary Clinic, Singapore, 270021 Singapore
                Author information
                http://orcid.org/0000-0001-5696-1407
                Article
                Publisher ID: 3198
                DOI: 10.1186/s13287-022-03198-z
                PMC ID: 9663191
                PubMed ID: 36376945
                SO-VID: 8fb72e0b-8e26-4415-a660-1b8046af2985
                Copyright © © The Author(s) 2022
                License:

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                Date received : 13 May 2022
                Date accepted : 26 October 2022
                Funding
                Funded by: National University Health System
                Award ID: NUHSRO/2019/085/adhoc funding for cell therapy
                Award ID: biotechnology
                Award Recipient :
                Funded by: Industry Liaison Office of the National University of Singapore
                Award ID: TAP2002019-04-02
                Award Recipient :
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2022

                ScienceOpen disciplines: Molecular medicine
                Keywords: cryopreservation,engineered mesenchymal stem cells,prodrug therapy
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: cryopreservation, engineered mesenchymal stem cells, prodrug therapy

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