Hypoxia‐induced increase in Sug1 leads to poor post‐transplantation survival of allogeneic mesenchymal stem cells

Autor: Ejlal Abu-El-Rub, Sanjiv Dhingra, Asmaa Mohammed ShamsEldeen, Glen Lester Sequiera, Hania Ibrahim Ammar, Niketa Sareen, Meenal Moudgil, Ilan Rubinchik, Weiang Yan, Laila A. Rashed, Heba S. Shokry
Rok vydání: 2020
Předmět:
0301 basic medicine
Proteasome Endopeptidase Complex
Cell
chemical and pharmacologic phenomena
Immune Privilege
Mesenchymal Stem Cell Transplantation
Major histocompatibility complex
Biochemistry
Rats
Sprague-Dawley
03 medical and health sciences
0302 clinical medicine
Immune system
Downregulation and upregulation
Antigen
Leukocytes
Genetics
medicine
CIITA
Animals
Humans
Rats
Wistar
Hypoxia
Molecular Biology
Cells
Cultured
biology
business.industry
Mesenchymal stem cell
Histocompatibility Antigens Class II
Nuclear Proteins
Mesenchymal Stem Cells
Rats
3. Good health
Transplantation
030104 developmental biology
medicine.anatomical_structure
Gene Knockdown Techniques
Trans-Activators
Cancer research
biology.protein
ATPases Associated with Diverse Cellular Activities
business
030217 neurology & neurosurgery
Biotechnology
Zdroj: The FASEB Journal. 34:12860-12876
ISSN: 1530-6860
0892-6638
DOI: 10.1096/fj.202000454r
Popis: Allogeneic mesenchymal stem cells (MSCs) from young and healthy donors are immunoprivileged and have the potential to treat numerous degenerative diseases. However, recent reviews of clinical trials report poor long-term survival of transplanted cells in the recipient that turned down the enthusiasm regarding MSC therapies. Increasing evidence now confirm that though initially immunoprivileged, MSCs eventually become immunogenic after transplantation in the ischemic or hypoxic environment of diseased tissues and are rejected by the host immune system. We performed in vitro (in rat and human cells) and in vivo (in a rat model) investigations to understand the mechanisms of the immune switch in the phenotype of MSCs. The immunoprivilege of MSCs is preserved by the absence of cell surface immune antigen, major histocompatibility complex II (MHC-II) molecule. We found that the ATPase subunit of 19S proteasome "Sug1" regulates MHC-II biosynthesis in MSCs. Exposure to hypoxia upregulates Sug1 in MSCs and its binding to class II transactivator (CIITA), a coactivator of MHC-II transcription. Sug1 binding to CIITA in hypoxic MSCs promotes the acetylation and K63 ubiquitination of CIITA leading to its activation and translocation to the nucleus, and ultimately MHC-II upregulation. In both rat and human MSCs, knocking down Sug1 inactivated MHC-II and preserved immunoprivilege even following hypoxia. In a rat model of myocardial infarction, transplantation of Sug1-knockdown MSCs in ischemic heart preserved immunoprivilege and improved the survival of transplanted cells. Therefore, the current study provides novel mechanisms of post-transplantation loss of immunoprivilege of MSCs. This study may help in facilitating better planning for future clinical trials.
Databáze: OpenAIRE
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