Stem Cell Biology, Laboratory, National Institute of Immunology, New Delhi, India.
Experimental Animal Facility, National Institute of Immunology, New Delhi, India.
Hepatology. 2017 Apr;65(4):1319-1335. doi: 10.1002/hep.29027. Epub 2017 Feb 25.
Alpha-1-antitrypsin (AAT) deficiency (AATD) is a genetic disease, caused by mutation of the AAT gene. Accumulation of mutated AAT protein aggregates in hepatocytes leads to endoplasmic reticulum stress, resulting in impairment of liver functions and, in some cases, hepatocellular carcinoma, whereas decline of AAT levels in sera is responsible for pulmonary emphysema. In advanced liver disease, the only option for treatment is liver transplantation, whereas AAT replacement therapy is therapeutic for emphysema. Given that hepatocytes are the primary affected cells in AATD, we investigated whether transplantation of bone marrow (BM)-derived stem cells in transgenic mice expressing human AATZ (the Z variant of AAT) confers any competitive advantages compared to host cells that could lead to pathological improvement. Mouse BM progenitors and human mesenchymal stem cells (MSCs) appeared to contribute in replacement of 40% and 13% host hepatocytes, respectively. Transplantation of cells resulted in decline of globule-containing hepatocytes, improvement in proliferation of globule-devoid hepatocytes from the host-derived hepatocytes, and apparently, donor-derived cells. Further analyses revealed that transplantation partially improves liver pathology as reflected by inflammatory response, fibrosis, and apoptotic death of hepatocytes. Cell therapy was also found to improve liver glycogen storage and sera glucose level in mice expressing human AATZ mice. These overall improvements in liver pathology were not restricted to transplantation of mouse BM cells. Preliminary results also showed that following transplantation of human BM-derived MSCs, globule-containing hepatocytes declined and donor-derived cells expressed human AAT protein.
These results suggest that BM stem cell transplantation may be a promising therapy for AATD-related liver disease. (Hepatology 2017;65:1319-1335).
α-1-抗胰蛋白酶（AAT）缺乏症（AATD）是一种遗传性疾病，由 AAT 基因突变引起。突变的 AAT 蛋白聚集体在肝细胞中积累，导致内质网应激，从而损害肝功能，在某些情况下还会导致肝细胞癌，而血清中 AAT 水平的下降则导致肺气肿。在晚期肝病中，唯一的治疗选择是肝移植，而 AAT 替代疗法是治疗肺气肿的方法。鉴于 AATD 中肝细胞是主要受影响的细胞，我们研究了在表达人 AATZ（AAT 的 Z 变体）的转基因小鼠中移植骨髓（BM）衍生的干细胞是否与宿主细胞相比具有任何竞争优势，从而导致病理改善。小鼠 BM 祖细胞和人间充质干细胞（MSCs）似乎分别有助于替代 40%和 13%的宿主肝细胞。细胞移植导致含球蛋白的肝细胞减少，宿主来源的肝细胞和明显的供体来源的细胞中无球蛋白肝细胞的增殖得到改善。进一步的分析表明，细胞移植部分改善了肝脏病理，表现为炎症反应、纤维化和肝细胞凋亡。还发现细胞治疗可改善表达人 AATZ 小鼠的肝糖原储存和血清葡萄糖水平。这些肝脏病理的总体改善不仅限于移植小鼠 BM 细胞。初步结果还表明，移植人 BM 来源的 MSCs 后，含球蛋白的肝细胞减少，供体来源的细胞表达人 AAT 蛋白。
这些结果表明，BM 干细胞移植可能是治疗 AATD 相关肝病的一种有前途的方法。（《肝脏病学》2017；65:1319-1335）。
