Bone marrow stem cell therapy partially ameliorates pathological consequences in livers of mice expressing mutant human α1-antitrypsin.

Research paper by Prakash P Baligar, Veena V Kochat, Shailendra K SK Arindkar, Zaffar Z Equbal, Snehashish S Mukherjee, Swati S Patel, Perumal P Nagarajan, Sujata S Mohanty, Jeffrey H JH Teckman, Asok A Mukhopadhyay

Indexed on: 06 Jan '17Published on: 06 Jan '17Published in: Hepatology


Alpha1-antitrypsin 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 (ER) 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 critical cases of liver ailments, the only option for treatment is liver transplantation, whereas AAT replacement therapy is followed in case of emphysema. As hepatocytes are the primary affected cells in AATD, we investigated whether transplantation of bone marrow-derived stem cells in transgenic mice expressing human AATZ (the Z variant of AAT) confers any competitive advantages compared to host cells for pathological improvement, if any. Mouse bone marrow (BM) progenitors and human mesenchymal stem cells (MSCs) appear 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 potentially donor-derived cells, as compared to AATZ globule containing hepatocytes. Further analyses revealed that transplantation partially improves liver pathology in terms of inflammatory response, fibrosis and apoptotic death of hepatocytes. Cell therapy was also found to improve liver glycogen storage and sera glucose level in the PiZ mice. These overall improvements in liver pathology were not restricted to the transplantation of mouse BM cells. Preliminary results also showed that in the case of human BM-derived MSCs the globule-containing hepatocytes declined and donor-derived cells expressed human AAT protein.These results suggest that bone marrow stem cell transplantation may be a promising therapy in the future for AATD related liver disease. This article is protected by copyright. All rights reserved.