Adipose tissue-derived human mesenchymal stromal cells can better suppress complement lysis, engraft and inhibit acute graft-versus-host disease in mice
Abstract Background Acute graft-versus-host disease (aGvHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). Transplantation of immunosuppressive human mesenchymal stromal cells (hMSCs) can protect against aGvHD post-HSCT; however, their efficacy is li...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-06-01
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| Series: | Stem Cell Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13287-023-03380-x |
| _version_ | 1797778996707983360 |
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| author | Stanley Chun Ming Wu Manyu Zhu Stanley C. C. Chik Maxwell Kwok Asif Javed Laalaa Law Shing Chan Kenneth R. Boheler Yin Ping Liu Godfrey Chi Fung Chan Ellen Ngar-Yun Poon |
| author_facet | Stanley Chun Ming Wu Manyu Zhu Stanley C. C. Chik Maxwell Kwok Asif Javed Laalaa Law Shing Chan Kenneth R. Boheler Yin Ping Liu Godfrey Chi Fung Chan Ellen Ngar-Yun Poon |
| author_sort | Stanley Chun Ming Wu |
| collection | DOAJ |
| description | Abstract Background Acute graft-versus-host disease (aGvHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). Transplantation of immunosuppressive human mesenchymal stromal cells (hMSCs) can protect against aGvHD post-HSCT; however, their efficacy is limited by poor engraftment and survival. Moreover, infused MSCs can be damaged by activated complement, yet strategies to minimise complement injury of hMSCs and improve their survival are limited. Methods Human MSCs were derived from bone marrow (BM), adipose tissue (AT) and umbilical cord (UC). In vitro immunomodulatory potential was determined by co-culture experiments between hMSCs and immune cells implicated in aGvHD disease progression. BM-, AT- and UC-hMSCs were tested for their abilities to protect aGvHD in a mouse model of this disease. Survival and clinical symptoms were monitored, and target tissues of aGvHD were examined by histopathology and qPCR. Transplanted cell survival was evaluated by cell tracing and by qPCR. The transcriptome of BM-, AT- and UC-hMSCs was profiled by RNA-sequencing. Focused experiments were performed to compare the expression of complement inhibitors and the abilities of hMSCs to resist complement lysis. Results Human MSCs derived from three tissues divergently protected against aGvHD in vivo. AT-hMSCs preferentially suppressed complement in vitro and in vivo, resisted complement lysis and survived better after transplantation when compared to BM- and UC-hMSCs. AT-hMSCs also prolonged survival and improved the symptoms and pathological features of aGvHD. We found that complement-decay accelerating factor (CD55), an inhibitor of complement, is elevated in AT-hMSCs and contributed to reduced complement activation. We further report that atorvastatin and erlotinib could upregulate CD55 and suppress complement in all three types of hMSCs. Conclusion CD55, by suppressing complement, contributes to the improved protection of AT-hMSCs against aGvHD. The use of AT-hMSCs or the upregulation of CD55 by small molecules thus represents promising new strategies to promote hMSC survival to improve the efficacy of transplantation therapy. As complement injury is a barrier to all types of hMSC therapy, our findings are of broad significance to enhance the use of hMSCs for the treatment of a wide range of disorders. |
| first_indexed | 2024-03-12T23:25:28Z |
| format | Article |
| id | doaj.art-af6eaade0f0e4bf4ab3f76f787552470 |
| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-03-12T23:25:28Z |
| publishDate | 2023-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj.art-af6eaade0f0e4bf4ab3f76f7875524702023-07-16T11:11:10ZengBMCStem Cell Research & Therapy1757-65122023-06-0114111610.1186/s13287-023-03380-xAdipose tissue-derived human mesenchymal stromal cells can better suppress complement lysis, engraft and inhibit acute graft-versus-host disease in miceStanley Chun Ming Wu0Manyu Zhu1Stanley C. C. Chik2Maxwell Kwok3Asif Javed4Laalaa Law5Shing Chan6Kenneth R. Boheler7Yin Ping Liu8Godfrey Chi Fung Chan9Ellen Ngar-Yun Poon10Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong KongDepartment of Orthopaedics and Traumatology, LKS Faculty of Medicine, The University of Hong KongDepartment of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong KongDepartment of Medicine and Therapeutics, The Chinese University of Hong KongSchool of Biomedical Science, LKS Faculty of Medicine, The University of Hong KongDepartment of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong KongDepartment of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong KongDivision of Cardiology, Department of Medicine and Department of Biomedical Engineering, The Johns Hopkins UniversityDepartment of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong KongDepartment of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong KongHong Kong Hub of Paediatric Excellence (HK HOPE), The Chinese University of Hong KongAbstract Background Acute graft-versus-host disease (aGvHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). Transplantation of immunosuppressive human mesenchymal stromal cells (hMSCs) can protect against aGvHD post-HSCT; however, their efficacy is limited by poor engraftment and survival. Moreover, infused MSCs can be damaged by activated complement, yet strategies to minimise complement injury of hMSCs and improve their survival are limited. Methods Human MSCs were derived from bone marrow (BM), adipose tissue (AT) and umbilical cord (UC). In vitro immunomodulatory potential was determined by co-culture experiments between hMSCs and immune cells implicated in aGvHD disease progression. BM-, AT- and UC-hMSCs were tested for their abilities to protect aGvHD in a mouse model of this disease. Survival and clinical symptoms were monitored, and target tissues of aGvHD were examined by histopathology and qPCR. Transplanted cell survival was evaluated by cell tracing and by qPCR. The transcriptome of BM-, AT- and UC-hMSCs was profiled by RNA-sequencing. Focused experiments were performed to compare the expression of complement inhibitors and the abilities of hMSCs to resist complement lysis. Results Human MSCs derived from three tissues divergently protected against aGvHD in vivo. AT-hMSCs preferentially suppressed complement in vitro and in vivo, resisted complement lysis and survived better after transplantation when compared to BM- and UC-hMSCs. AT-hMSCs also prolonged survival and improved the symptoms and pathological features of aGvHD. We found that complement-decay accelerating factor (CD55), an inhibitor of complement, is elevated in AT-hMSCs and contributed to reduced complement activation. We further report that atorvastatin and erlotinib could upregulate CD55 and suppress complement in all three types of hMSCs. Conclusion CD55, by suppressing complement, contributes to the improved protection of AT-hMSCs against aGvHD. The use of AT-hMSCs or the upregulation of CD55 by small molecules thus represents promising new strategies to promote hMSC survival to improve the efficacy of transplantation therapy. As complement injury is a barrier to all types of hMSC therapy, our findings are of broad significance to enhance the use of hMSCs for the treatment of a wide range of disorders.https://doi.org/10.1186/s13287-023-03380-xHuman mesenchymal stromal cellsAcute graft-versus-host diseaseCD55ComplementhMSC transplantationhMSC |
| spellingShingle | Stanley Chun Ming Wu Manyu Zhu Stanley C. C. Chik Maxwell Kwok Asif Javed Laalaa Law Shing Chan Kenneth R. Boheler Yin Ping Liu Godfrey Chi Fung Chan Ellen Ngar-Yun Poon Adipose tissue-derived human mesenchymal stromal cells can better suppress complement lysis, engraft and inhibit acute graft-versus-host disease in mice Stem Cell Research & Therapy Human mesenchymal stromal cells Acute graft-versus-host disease CD55 Complement hMSC transplantation hMSC |
| title | Adipose tissue-derived human mesenchymal stromal cells can better suppress complement lysis, engraft and inhibit acute graft-versus-host disease in mice |
| title_full | Adipose tissue-derived human mesenchymal stromal cells can better suppress complement lysis, engraft and inhibit acute graft-versus-host disease in mice |
| title_fullStr | Adipose tissue-derived human mesenchymal stromal cells can better suppress complement lysis, engraft and inhibit acute graft-versus-host disease in mice |
| title_full_unstemmed | Adipose tissue-derived human mesenchymal stromal cells can better suppress complement lysis, engraft and inhibit acute graft-versus-host disease in mice |
| title_short | Adipose tissue-derived human mesenchymal stromal cells can better suppress complement lysis, engraft and inhibit acute graft-versus-host disease in mice |
| title_sort | adipose tissue derived human mesenchymal stromal cells can better suppress complement lysis engraft and inhibit acute graft versus host disease in mice |
| topic | Human mesenchymal stromal cells Acute graft-versus-host disease CD55 Complement hMSC transplantation hMSC |
| url | https://doi.org/10.1186/s13287-023-03380-x |
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