Hypoimmunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients
Open accessAbstract
Autologous induced pluripotent stem cells (iPSCs) constitute an unlimited cell source for patient-specific cell-based organ repair strategies. However, their generation and subsequent differentiation into specific cells or tissues entail cell line-specific manufacturing challenges and form a lengthy process that precludes acute treatment modalities. These shortcomings could be overcome by using prefabricated allogeneic cell or tissue products, but the vigorous immune response against histo-incompatible cells has prevented the successful implementation of this approach. Here we show that both mouse and human iPSCs lose their immunogenicity when major histocompatibility complex (MHC) class I and II genes are inactivated and CD47 is over-expressed. These hypoimmunogenic iPSCs retain their pluripotent stem cell potential and differentiation capacity. Endothelial cells, smooth muscle cells, and cardiomyocytes derived from hypoimmunogenic mouse or human iPSCs reliably evade immune rejection in fully MHC-mismatched allogeneic recipients and survive long-term without the use of immunosuppression. These findings suggest that hypoimmunogenic cell grafts can be engineered for universal transplantation.
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Gene-edited iPSCs with B2M and CIITA deleted and CD47 overexpressed differentiated into endothelial cells and cardiomyocytes that demonstrated long-term survival in humanized mouse models without any immunosuppression.
“These gene-edited iPSCs could differentiate into endothelial cells and cardiomyocytes that demonstrated long-term survival in humanized mouse models without any immunosuppression.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [118]
Overexpression of CD47 has been successfully implemented to mitigate innate immune responses after HLA deletion.
“Overexpression of CD47 has also been successfully implemented to mitigate innate immune responses after HLA deletion.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [118]
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- Authors
- Deuse, T., Hu, X., Gravina, A., Wang, D., Tediashvili, G., De, C., Thayer, W. O., Wahl, A., Garcia, J. V., Reichenspurner, H., Davis, M. M., Lanier, L. L., & Schrepfer, S.
- Affiliations
- University of California, San Francisco (US)
- Universität Hamburg (DE)
- University of North Carolina at Chapel Hill (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Schrepfer, Sonja
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2019-02-18
- Volume
- 37
- Issue
- 3
- Pages
- 252-258
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC6419516
- OpenAlex
- W2911604931
- Cited by
- 758
- References
- 31
- Citations by year
- 2026: 98 · 2025: 102 · 2024: 102 · 2023: 113 · 2022: 94 · 2021: 97 · 2020: 106 · 2019: 46
- FWCI
- 28.36
- Type
- journal article
- Language
- en
- Update notices
- correction (2022-09-16)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL140236)
- National Institute of Mental Health (R01MH108179)
- National Institute of Allergy and Infectious Diseases (R01AI068129, R01AI111899, R01AI123010, U19AI057229)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Transplantation › Organ and Tissue Transplantation Research
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- induced pluripotent stem cells, immune rejection, allogeneic transplantation, MHC mismatch, endothelial cells, smooth muscle cells, cardiomyocytes, immunosuppression-free transplantation
- MeSH terms
- Animals, Cell Differentiation, Graft Rejection, HLA Antigens, Humans, Transplantation, Homologous, Histocompatibility Antigens Class I, Myocytes, Cardiac, Mice, Induced Pluripotent Stem Cells
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