Hypoimmune induced pluripotent stem cell–derived cell therapeutics treat cardiovascular and pulmonary diseases in immunocompetent allogeneic mice

The emerging field of regenerative cell therapy is still limited by the fewcell types that can reliably be differentiated frompluripotent stem cells and by the immune hurdle of commercially scalable allogeneic cell therapeutics. Here, we show that gene-edited, immune-evasive cell grafts can survive...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2021-07, Vol.118 (28), p.1-11
Main Authors: Deuse, Tobias, Tediashvili, Grigol, Hu, Xiaomeng, Gravina, Alessia, Tamenang, Annika, Wang, Dong, Connolly, Andrew, Mueller, Christian, Mallavia, Beñat, Looney, Mark R., Alawi, Malik, Lanier, Lewis L., Schrepfer, Sonja
Format: Article
Language:English
Subjects:
alpha 1-Antitrypsin - metabolism
Animals
Biological Sciences
Cardiomyocytes
Cardiovascular Diseases - immunology
Cardiovascular Diseases - therapy
Cell differentiation
Cell therapy
Congestive heart failure
Endothelial cells
Endothelial Cells - transplantation
Genetic modification
Heart Failure - therapy
Hemodynamics
Hindlimb - blood supply
Hindlimb - pathology
Immunocompetence
Induced Pluripotent Stem Cells - immunology
Ischemia
Ischemia - pathology
Lung diseases
Lung Diseases - immunology
Lung Diseases - therapy
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Myocytes, Cardiac - transplantation
Perfusion
Pluripotency
Serum levels
Stem Cell Transplantation
Stem cells
Structure-function relationships
Therapy
Transplantation, Homologous
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Summary:The emerging field of regenerative cell therapy is still limited by the fewcell types that can reliably be differentiated frompluripotent stem cells and by the immune hurdle of commercially scalable allogeneic cell therapeutics. Here, we show that gene-edited, immune-evasive cell grafts can survive and successfully treat diseases in immunocompetent, fully allogeneic recipients. Transplanted endothelial cells improved perfusion and increased the likelihood of limb preservation in mice with critical limb ischemia. Endothelial cell grafts transduced to express a transgene for alpha1-antitrypsin (A1AT) successfully restored physiologic A1AT serum levels in mice with genetic A1AT deficiency. This cell therapy prevented both structural and functional changes of emphysematous lung disease. A mixture of endothelial cells and cardiomyocytes was injected into infarcted mouse hearts, and both cell types orthotopically engrafted in the ischemic areas. Cell therapy led to an improvement in invasive hemodynamic heart failure parameters. Our study supports the development of hypoimmune, universal regenerative cell therapeutics for cost-effective treatments of major diseases.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2022091118