Center for Neuroregeneration Research, Harvard Medical School/McLean Hospital, Belmont, Massachusetts 02478, USA.
Stem Cells. 2011 Jul;29(7):1052-63. doi: 10.1002/stem.662.
Immune rejection and risk of tumor formation are perhaps the greatest hurdles in the field of stem cell transplantation. Here, we report the generation of several lines of induced pluripotent stem cells (iPSCs) from cynomolgus macaque (CM) skin fibroblasts carrying specific major histocompatibility complex (MHC) haplotypes. To develop a collection of MHC-matched iPSCs, we genotyped the MHC locus of 25 CMs by microsatellite polymerase chain reaction analysis. Using retroviral infection of dermal skin fibroblasts, we generated several CM-iPSC lines carrying different haplotypes. We characterized the immunological properties of CM-iPSCs and demonstrated that CM-iPSCs can be induced to differentiate in vitro along specific neuronal populations, such as midbrain dopaminergic (DA) neurons. Midbrain-like DA neurons generated from CM-iPSCs integrated into the striatum of a rodent model of Parkinson's disease and promoted behavioral recovery. Importantly, neither tumor formation nor inflammatory reactions were observed in the transplanted animals up to 6 months after transplantation. We believe that the generation and characterization of such histocompatible iPSCs will allow the preclinical validation of safety and efficacy of iPSCs for neurodegenerative diseases and several other human conditions in the field of regenerative medicine.
免疫排斥和肿瘤形成的风险可能是干细胞移植领域最大的障碍。在这里，我们报告了从携带特定主要组织相容性复合体（MHC）单倍型的食蟹猴（CM）皮肤成纤维细胞中生成了几株诱导多能干细胞（iPSC）。为了开发一组 MHC 匹配的 iPSC，我们通过微卫星聚合酶链反应分析对 25 只 CM 的 MHC 基因座进行了基因分型。通过真皮成纤维细胞的逆转录病毒感染，我们生成了几株携带不同单倍型的 CM-iPSC 系。我们对 CM-iPSC 的免疫学特性进行了表征，并证明 CM-iPSC 可以在体外诱导分化为特定的神经元群体，如中脑多巴胺能（DA）神经元。从中脑诱导而来的 DA 神经元分化而来的 CM-iPSC 整合到帕金森病啮齿动物模型的纹状体中，并促进了行为恢复。重要的是，在移植后 6 个月内，在移植动物中既没有观察到肿瘤形成，也没有观察到炎症反应。我们相信，此类组织相容性 iPSC 的生成和表征将允许在再生医学领域对神经退行性疾病和其他几种人类疾病的 iPSC 的安全性和有效性进行临床前验证。
