Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
EBioMedicine. 2019 Apr;42:443-457. doi: 10.1016/j.ebiom.2019.03.011. Epub 2019 Mar 26.
Comparing non-inbred autologous and allogeneic induced pluripotent stem cells (iPSCs) and their secreted subcellular products among non-human primates is critical for choosing optimal iPSC products for human clinical trials.
iPSCs were induced from skin fibroblastic cells of adult male rhesus macaques belonging to four unrelated consanguineous families. Teratoma generativity, host immune response, and skin wound healing promotion were evaluated subsequently.
All autologous, but no allogeneic, iPSCs formed teratomas, whereas all allogeneic, but no autologous, iPSCs caused lymphocyte infiltration. Macrophages were not detectable in any wound. iPSCs expressed significantly more MAMU A and E of the major histocompatibility complex (MHC) class I but not more other MHC genetic alleles than parental fibroblastic cells. All topically disseminated autologous and allogeneic iPSCs, and their exosomes accelerated skin wound healing, as demonstrated by wound closure, epithelial coverage, collagen deposition, and angiogenesis. Allogeneic iPSCs and their exosomes were less effective and viable than their autologous counterparts. Some iPSCs differentiated into new endothelial cells and all iPSCs lost their pluripotency in 14 days. Exosomes increased cell viability of injured epidermal, endothelial, and fibroblastic cells in vitro. Although exosomes contained some mRNAs of pluripotent factors, they did not impart pluripotency to host cells.
Although all of the autologous and allogeneic iPSCs and exosomes accelerated wound healing, allogeneic iPSC exosomes were the preferred choice for "off-the shelf" iPSC products, owing to their mass-production, with no concern of teratoma formation. FUND: National Natural Science Foundation of China and National Key R&D Program of China.
在非人类灵长类动物中比较非近亲同源的自体诱导多能干细胞（iPSC）和异体诱导多能干细胞及其分泌的亚细胞产物，对于选择最佳的 iPSC 产品用于人类临床试验至关重要。
从属于四个无亲缘关系的近亲家庭的成年雄性恒河猴的皮肤成纤维细胞中诱导 iPSC。随后评估畸胎瘤发生能力、宿主免疫反应和促进皮肤伤口愈合的能力。
所有自体 iPSC 都能形成畸胎瘤，但没有异体 iPSC 能形成；所有异体 iPSC 都能引起淋巴细胞浸润，但没有自体 iPSC 能引起淋巴细胞浸润。任何伤口都检测不到巨噬细胞。iPSC 表达的主要组织相容性复合体（MHC）I 类的 Mamu A 和 E 显著多于亲本成纤维细胞，但其他 MHC 遗传等位基因表达并不多于亲本成纤维细胞。所有局部播散的自体和异体 iPSC 及其外泌体都能加速皮肤伤口愈合，表现为伤口闭合、上皮覆盖、胶原沉积和血管生成。异体 iPSC 及其外泌体的效果和活力都不如其自体对应物。一些 iPSC 分化为新的内皮细胞，所有 iPSC 在 14 天内失去其多能性。外泌体增加了体外受损表皮、内皮和成纤维细胞的活力。尽管外泌体含有一些多能因子的 mRNA，但它们不能赋予宿主细胞多能性。
尽管所有的自体和异体 iPSC 及其外泌体都能加速伤口愈合，但由于异体 iPSC 外泌体可以大规模生产，且不会形成畸胎瘤，因此是“现成”iPSC 产品的首选。
国家自然科学基金和国家重点研发计划。
