Hypoimmune induced pluripotent stem cell-derived cell therapeutics treat cardiovascular and pulmonary diseases in immunocompetent allogeneic mice.
Hypoimmune induced pluripotent stem cell-derived cell therapeutics treat cardiovascular and pulmonary diseases in immunocompetent allogeneic mice.
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DOI：
10.1073/pnas.2022091118
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发表时间：
2021-07-13
影响因子：
11.1
通讯作者：
Schrepfer S
中科院分区：
文献类型：
--
作者：
Deuse T;Tediashvili G;Hu X;Gravina A;Tamenang A;Wang D;Connolly A;Mueller C;Mallavia B;Looney MR;Alawi M;Lanier LL;Schrepfer S
精确的基因编辑允许对免疫受体和配体进行工程改造，以降低细胞的免疫原性，目前正在开发产生免疫逃避性干细胞来源的策略。本文介绍了翻译方面产生普遍可移植的，疾病特异性，治疗性细胞产品。我们提供了概念证明，免疫工程细胞可以治疗完全同种异体受试者的主要心血管和肺部疾病，而无需使用任何免疫抑制。翻译方面的重点是显示临床相关的结果指标，这是广泛用于人体试验的改善。根据大规模生产通用细胞疗法的可行性，这种方法可以实现具有成本效益的细胞疗法。再生细胞疗法的新兴领域仍然受到可以可靠地从多能干细胞分化的少数细胞类型以及商业上可扩展的同种异体细胞疗法的免疫障碍的限制。在这里，我们证明了基因编辑的免疫逃避细胞移植物可以在免疫活性的完全同种异体受体中存活并成功治疗疾病。移植的内皮细胞改善了灌注，增加了严重肢体缺血小鼠肢体保存的可能性。内皮细胞移植物转导表达α 1-抗胰蛋白酶（A1 AT）的转基因，成功地恢复了生理A1 AT血清水平的遗传A1 AT缺乏症的小鼠。这种细胞疗法防止了肺气肿性肺病的结构和功能变化。将内皮细胞和心肌细胞的混合物注射到梗塞的小鼠心脏中，并将两种细胞类型原位移植到缺血区域。细胞治疗导致侵入性血流动力学心力衰竭参数的改善。我们的研究支持开发低免疫，通用再生细胞疗法，用于重大疾病的成本效益治疗。
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.
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影响因子：
3.9
作者：
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通讯作者：
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