Chamberlain Jason, Yamagami Takashi, Colletti Evan, Theise Neil D, Desai Jyoti, Frias Ana, Pixley John, Zanjani Esmail D, Porada Christopher D, Almeida-Porada Graça
Department of Animal Biotechnology, University of Nevada at Reno, Reno, NV 89557-0104, USA.
Hepatology. 2007 Dec;46(6):1935-45. doi: 10.1002/hep.21899.
Alternative methods to whole liver transplantation require a suitable cell that can be expanded to obtain sufficient numbers required for successful transplantation while maintaining the ability to differentiate into hepatocytes. Mesenchymal stem cells (MSCs) possess several advantageous characteristics for cell-based therapy and have been shown to be able to differentiate into hepatocytes. Thus, we investigated whether the intrahepatic delivery of human MSCs is a safe and effective method for generating human hepatocytes and whether the route of administration influences the levels of donor-derived hepatocytes and their pattern of distribution throughout the parenchyma of the recipient's liver. Human clonally derived MSCs were transplanted by an intraperitoneal (n = 6) or intrahepatic (n = 6) route into preimmune fetal sheep. The animals were analyzed 56-70 days after transplantation by immunohistochemistry, enzyme-linked immunosorbent assay, and flow cytometry. The intrahepatic injection of human MSCs was safe and resulted in more efficient generation of hepatocytes (12.5% +/- 3.5% versus 2.6% +/- 0.4%). The animals that received an intrahepatic injection exhibited a widespread distribution of hepatocytes throughout the liver parenchyma, whereas an intraperitoneal injection resulted in a preferential periportal distribution of human hepatocytes that produced higher amounts of albumin. Furthermore, hepatocytes were generated from MSCs without the need to first migrate/lodge to the bone marrow and give rise to hematopoietic cells.
Our studies provide evidence that MSCs are a valuable source of cells for liver repair and regeneration and that, by the alteration of the site of injection, the generation of hepatocytes occurs in different hepatic zones, suggesting that a combined transplantation approach may be necessary to successfully repopulate the liver with these cells.
全肝移植的替代方法需要一种合适的细胞，这种细胞能够扩增以获得成功移植所需的足够数量，同时保持分化为肝细胞的能力。间充质干细胞（MSCs）具有细胞治疗的几个有利特性，并且已被证明能够分化为肝细胞。因此，我们研究了人MSCs的肝内递送是否是产生人肝细胞的安全有效方法，以及给药途径是否会影响供体来源肝细胞的水平及其在受体肝脏实质中的分布模式。将人克隆来源的MSCs通过腹腔内（n = 6）或肝内（n = 6）途径移植到免疫前的胎羊中。在移植后56 - 70天，通过免疫组织化学、酶联免疫吸附测定和流式细胞术对动物进行分析。肝内注射人MSCs是安全的，并且导致更有效地产生肝细胞（12.5% ± 3.5%对2.6% ± 0.4%）。接受肝内注射的动物肝细胞在整个肝脏实质中广泛分布，而腹腔内注射导致人肝细胞优先在门静脉周围分布，产生更高量的白蛋白。此外，肝细胞由MSCs产生，无需先迁移/驻留在骨髓并产生造血细胞。
我们的研究提供了证据，表明MSCs是肝脏修复和再生的有价值的细胞来源，并且通过改变注射部位，肝细胞在不同的肝区产生，这表明可能需要联合移植方法才能用这些细胞成功地使肝脏重新填充。
