Uterine-derived progenitor cells are immunoprivileged and effectively improve cardiac regeneration when used for cell therapy.
Cell therapy to prevent cardiac dysfunction after myocardial infarction (MI) is less effective in aged patients because aged cells have decreased regenerative capacity. Allogeneic transplanted stem cells (SCs) from young donors are usually rejected. Maintaining transplanted SC immunoprivilege may dramatically improve regenerative outcomes. The uterus has distinct immune characteristics, and we showed that reparative uterine SCs home to the myocardium post-MI. Here, we identify immunoprivileged uterine SCs and assess their effects on cardiac regeneration after allogeneic transplantation. We found more than 20% of cells in the mouse uterus have undetectable MHC I expression by flow cytometry. Uterine MHC I((neg)) and MHC I((pos)) cells were separated by magnetic cell sorting. The MHC I((neg)) population expressed the SC markers CD34, Sca-1 and CD90, but did not express MHC II or c-kit. In vitro, MHC I((neg)) and ((pos)) SCs show colony formation and endothelial differentiation capacity. In mixed leukocyte co-culture, MHC I((neg)) cells showed reduced cell death and leukocyte proliferation compared to MHC I((pos)) cells. MHC I((neg)) and ((pos)) cells had significantly greater angiogenic capacity than mesenchymal stem cells. The benefits of intramyocardial injection of allogeneic MHC I((neg)) cells after MI were comparable to syngeneic bone marrow cell transplantation, with engraftment in cardiac tissue and limited recruitment of CD4 and CD8 cells up to 21 days post-MI. MHC I((neg)) cells preserved cardiac function, decreased infarct size and improved regeneration post-MI. This new source of immunoprivileged cells can induce neovascularization and could be used as allogeneic cell therapy for regenerative medicine.
Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, Canada.
Ana
A
Ludke
Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, Canada.
Jun
J
Wu
Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Canada.
Mansoreh
M
Nazari
Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Canada.
Kota
K
Hatta
Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, Canada; Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Zhengbo
Z
Shao
Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, Canada.
Shu-Hong
SH
Li
Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, Canada; Department of Anatomy, Shanxi Medical University, Taiyuan, China.
Huifang
H
Song
Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, Canada.
Nathan C
NC
Ni
Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Canada.
Richard D
RD
Weisel
Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Canada. Electronic address: renkeli@uhnresearch.ca.
Ren-Ke
RK
Li
D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D002921:Cicatrix / Q000150:complications / Q000473:pathology; D018920:Coculture Techniques; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006321:Heart / Q000503:physiopathology*; D006334:Heart Function Tests; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D009206:Myocardium / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000235:genetics; D012038:Regeneration; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology* / Q000276:immunology*; D014184:Transplantation, Homologous; D014599:Uterus / Q000166:cytology*; D014945:Wound Healing / Q000235:genetics
D000950:Antigens, Ly; D015395:Histocompatibility Antigens Class I; C074650:Ly6a protein, mouse; D008565:Membrane Proteins
Cell therapy; Immune tolerance; Myocardial infarction; Stem cell; Uterus