Espejel Silvia, Eckardt Sigrid, Harbell Jack, Roll Garrett R, McLaughlin K John, Willenbring Holger
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, San Francisco, California, USA; Department of Surgery, Division of Transplantation, University of California San Francisco, San Francisco, California, USA.
Stem Cells. 2014 Jul;32(7):1983-8. doi: 10.1002/stem.1726.
Parthenogenesis is the development of an oocyte without fertilization. Mammalian parthenogenetic (PG) embryos are not viable, but can develop into blastocysts from which embryonic stem cells (ESCs) have been derived in mouse and human. PG ESCs are frequently homozygous for alleles encoding major histocompatibility complex (MHC) molecules. MHC homozygosity permits much more efficient immune matching than MHC heterozygosity found in conventional ESCs, making PG ESCs a promising cell source for cell therapies requiring no or little immune suppression. However, findings of restricted differentiation and proliferation of PG cells in developmental chimeras have cast doubt on the potential of PG ESC derivatives for organ regeneration. To address this uncertainty, we determined whether PG ESC derivatives are effective in rescuing mice with lethal liver failure due to deficiency of fumarylacetoacetate hydrolase (Fah). In developmental chimeras generated by injecting wild-type PG ESCs into Fah-deficient blastocysts, PG ESCs differentiated into hepatocytes that could repopulate the liver, provide normal liver function, and facilitate long-term survival of adult mice. Moreover, after transplantation into adult Fah-deficient mice, PG ESC-derived hepatocytes efficiently engrafted and proliferated, leading to high-level liver repopulation. Our results show that--despite the absence of a paternal genome--PG ESCs can form therapeutically effective hepatocytes.
孤雌生殖是指未受精的卵母细胞发育过程。哺乳动物孤雌生殖（PG）胚胎无法存活，但可发育成囊胚，在小鼠和人类中已从这些囊胚中获得胚胎干细胞（ESC）。PG ESC的编码主要组织相容性复合体（MHC）分子的等位基因常为纯合子。与传统ESC中发现的MHC杂合性相比，MHC纯合性能实现更高效的免疫匹配，这使得PG ESC成为细胞疗法中无需或只需极少免疫抑制的有前景的细胞来源。然而，发育嵌合体中PG细胞分化和增殖受限的研究结果，让人对PG ESC衍生物用于器官再生的潜力产生怀疑。为解决这一不确定性，我们确定了PG ESC衍生物是否能有效拯救因富马酰乙酰乙酸水解酶（Fah）缺乏而导致致命性肝衰竭的小鼠。在将野生型PG ESC注入Fah缺陷囊胚产生的发育嵌合体中，PG ESC分化为肝细胞，这些肝细胞可重新填充肝脏、提供正常肝功能并促进成年小鼠的长期存活。此外，将PG ESC来源的肝细胞移植到成年Fah缺陷小鼠体内后，它们能有效植入并增殖，从而实现高水平的肝脏再填充。我们的结果表明，尽管没有父本基因组，PG ESC仍可形成具有治疗效果的肝细胞。
