期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：28
DOI：10.1073/pnas.2022091118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Precise gene editing allows engineering of immune receptors and ligands to reduce the immunogenicity of cells, and strategies for the generation of immune-evasive stem cell sources are currently being developed. This article describes the translational aspect of generating universally transplantable, disease-specific, therapeutic cell products. We provide proof of concept that immune-engineered cells can treat major cardiovascular and pulmonary diseases in fully allogeneic subjects without utilizing any immunosuppression. The translational aspect is emphasized by showing improvements in clinically relevant outcome measures, which are widely used in human trials. Depending on the feasibility of large-scale manufacturing of universal cell therapeutics, this approach could enable cost-effective cell therapy.
The emerging field of regenerative cell therapy is still limited by the few cell types that can reliably be differentiated from pluripotent 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.
