Abstract
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.
Highlights
Introduction105 day 7 100 P < 0.0001 iPSC-derived endothelial cells (iECs) day 14 100
105 day 7 100 P < 0.0001 induced pluripotent stem cell (iPSC)-derived endothelial cells (iECs) day 14 100P = 0.0028 no cells alloPerfusion units Perfusion units allogeneic B6HIP (alloHIP) iECs in BALB/c 1.0×103 Days day 21 100iaEllCoHs IP iaElClosHIPDAPI Luciferase VE-cadherinPercent of animalsG 5 normal 4 pale foot or gait abnormalities 3 gangrene < half foot, no lower limb muscle necrosis 2 gangrene < half foot, + lower limb muscle necrosis 1 gangrene > half foot 0 loss > half lower limb P = 0.0001 100 no cellasllo iaEllCosHIP iECs allo iECs μm alloHIP iECs μm Emphysematous Lungs
II expression and Cd47 was overexpressed using lentiviral transduction. These B6HIP iPSCs as well as their parental B6 iPSCs were transduced to express firefly luciferase (FLuc) for subsequent bioluminescence imaging (BLI) studies to quantitatively assess their survival after transplantation
Summary
105 day 7 100 P < 0.0001 iECs day 14 100. Perfusion units Perfusion units alloHIP iECs in BALB/c 1.0×103 Days day 21 100. G 5 normal 4 pale foot or gait abnormalities 3 gangrene < half foot, no lower limb muscle necrosis 2 gangrene < half foot, + lower limb muscle necrosis 1 gangrene > half foot 0 loss > half lower limb P = 0.0001 100 no cellasllo iaEllCosHIP iECs allo iECs μm alloHIP iECs μm Emphysematous Lungs
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