PMID- 32499535
OWN - NLM
STAT- MEDLINE
DCOM- 20210319
LR  - 20210604
IS  - 2041-4889 (Electronic)
VI  - 11
IP  - 6
DP  - 2020 Jun 4
TI  - Hypoxia-induced shift in the phenotype of proteasome from 26S toward 
      immunoproteasome triggers loss of immunoprivilege of mesenchymal stem cells.
PG  - 419
LID - 10.1038/s41419-020-2634-6 [doi]
LID - 419
AB  - Allogeneic mesenchymal stem cells (MSCs) are immunoprivileged and are being 
      investigated in phase I and phase II clinical trials to treat different 
      degenerative and autoimmune diseases. In spite of encouraging outcome of initial 
      trials, the long-term poor survival of transplanted cells in the host tissue has 
      declined the overall enthusiasm. Recent analyses of allogeneic MSCs based studies 
      confirm that after transplantation in the hypoxic or ischemic microenvironment of 
      diseased tissues, MSCs become immunogenic and are rejected by recipient immune 
      system. The immunoprivilege of MSCs is preserved by absence or negligible 
      expression of cell surface antigen, human leukocyte antigen (HLA)-DRalpha. We found 
      that in normoxic MSCs, 26S proteasome degrades HLA-DRalpha and maintains 
      immunoprivilege of MSCs. The exposure to hypoxia leads to inactivation of 26S 
      proteasome and formation of immunoproteasome in MSCs, which is associated with 
      upregulation and activation of HLA-DRalpha, and as a result, MSCs become immunogenic. 
      Furthermore, inhibition of immunoproteasome formation in hypoxic MSCs preserves 
      the immunoprivilege. Therefore, hypoxia-induced shift in the phenotype of 
      proteasome from 26S toward immunoproteasome triggers loss of immunoprivilege of 
      allogeneic MSCs. The outcome of the current study may provide molecular targets 
      to plan interventions to preserve immunoprivilege of allogeneic MSCs in the 
      hypoxic or ischemic environment.
FAU - Abu-El-Rub, Ejlal
AU  - Abu-El-Rub E
AUID- ORCID: 0000-0001-9217-2560
AD  - Institute of Cardiovascular Sciences, St. Boniface General Hospital Research 
      Centre, Regenerative Medicine Program, Department of Physiology and 
      Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, 
      Winnipeg, MB, R2H2A6, Canada.
FAU - Sareen, Niketa
AU  - Sareen N
AD  - Institute of Cardiovascular Sciences, St. Boniface General Hospital Research 
      Centre, Regenerative Medicine Program, Department of Physiology and 
      Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, 
      Winnipeg, MB, R2H2A6, Canada.
FAU - Yan, Weiang
AU  - Yan W
AD  - Institute of Cardiovascular Sciences, St. Boniface General Hospital Research 
      Centre, Regenerative Medicine Program, Department of Physiology and 
      Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, 
      Winnipeg, MB, R2H2A6, Canada.
FAU - Alagarsamy, Keshav Narayan
AU  - Alagarsamy KN
AD  - Institute of Cardiovascular Sciences, St. Boniface General Hospital Research 
      Centre, Regenerative Medicine Program, Department of Physiology and 
      Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, 
      Winnipeg, MB, R2H2A6, Canada.
FAU - Rafieerad, Alireza
AU  - Rafieerad A
AD  - Institute of Cardiovascular Sciences, St. Boniface General Hospital Research 
      Centre, Regenerative Medicine Program, Department of Physiology and 
      Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, 
      Winnipeg, MB, R2H2A6, Canada.
FAU - Srivastava, Abhay
AU  - Srivastava A
AD  - Institute of Cardiovascular Sciences, St. Boniface General Hospital Research 
      Centre, Regenerative Medicine Program, Department of Physiology and 
      Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, 
      Winnipeg, MB, R2H2A6, Canada.
FAU - Desiderio, Vincenzo
AU  - Desiderio V
AD  - Department of Experimental Medicine, University of Campania Luigi Vanvitelli, 
      80138, Naples, Italy.
FAU - Dhingra, Sanjiv
AU  - Dhingra S
AUID- ORCID: 0000-0002-2664-7633
AD  - Institute of Cardiovascular Sciences, St. Boniface General Hospital Research 
      Centre, Regenerative Medicine Program, Department of Physiology and 
      Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, 
      Winnipeg, MB, R2H2A6, Canada. sdhingra@sbrc.ca.
LA  - eng
GR  - PJT156148/CIHR/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200604
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (HLA-DR alpha-Chains)
RN  - 0 (Protein Subunits)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
RN  - EC 3.4.99.- (ATP dependent 26S protease)
SB  - IM
MH  - Cell Hypoxia/immunology
MH  - Down-Regulation
MH  - HLA-DR alpha-Chains/metabolism
MH  - Humans
MH  - Mesenchymal Stem Cells/*immunology/*pathology
MH  - Phenotype
MH  - Proteasome Endopeptidase Complex/*immunology
MH  - Protein Subunits/metabolism
MH  - Proteolysis
MH  - Up-Regulation
PMC - PMC7272449
COIS- The authors declare that they have no conflict of interest.
EDAT- 2020/06/06 06:00
MHDA- 2021/03/20 06:00
PMCR- 2020/06/04
CRDT- 2020/06/06 06:00
PHST- 2019/12/18 00:00 [received]
PHST- 2020/05/05 00:00 [accepted]
PHST- 2020/05/01 00:00 [revised]
PHST- 2020/06/06 06:00 [entrez]
PHST- 2020/06/06 06:00 [pubmed]
PHST- 2021/03/20 06:00 [medline]
PHST- 2020/06/04 00:00 [pmc-release]
AID - 10.1038/s41419-020-2634-6 [pii]
AID - 2634 [pii]
AID - 10.1038/s41419-020-2634-6 [doi]
PST - epublish
SO  - Cell Death Dis. 2020 Jun 4;11(6):419. doi: 10.1038/s41419-020-2634-6.