Engineered Liver Progenitors as a Novel Treatment for Acute Liver Injury

Review of “Downregulation of ALR impairs the therapeutic efficacy of LEPCs against acute liver injury by enhancing mitochondrial fission” from STEM CELLS by Stuart P. Atkinson

Mouse liver epithelial progenitor cells can self-renew and differentiate into hepatocytes and cholangiocytes [1] (See the related STEM CELLS article for more!), and recent studies have shown their ability to engraft into the injured liver and restore/protect liver function [2-4]; however, problems related to post-transplantation survival and homing [5] may represent obstacles to their widespread clinical use.

Researchers led by Wei An (Capital Medical University, Beijing, China) sought to explore methods to improve the therapeutic efficacy of liver epithelial progenitor cells, and they recently turned to the expression of augmenter of liver regeneration (ALR), which can stimulate hepatic regeneration [6] and prevent ischemia-reperfusion injury [7-9]. In their recent STEM CELLS article, Dong et al. set out to discover whether the ectopic expression of ALR in liver epithelial progenitor cells could enhance their therapeutic potential and protect mice against acute liver injury [10].

The authors discovered that the intrasplenic transplantation of ALR-expressing liver epithelial progenitor cells following the induction of acute liver injury in mice (through the administration of tetrachloromethane) relieved mice of hepatic tissue injury and attenuated inflammatory cell infiltration, suggesting that the modified cells protected against further disease development. Further in vivo studies established that intrasplenically transplanted ALR-expressing liver epithelial progenitor cells displayed a significantly improved ability to home to the injured liver of acute liver injury model mice through the SDF-1/CXCR4 signaling axis.

Finally, in vitro mechanistic studies revealed that ALR expression in liver epithelial progenitor cells facilitated stemness by inhibiting the phosphorylation of dynamin-related protein 1 (DRP1), which helps to maintain mitochondrial integrity and cellular bioenergetics and inhibit apoptosis.

Overall, this fascinating study suggests that engineered liver epithelial progenitor cells may represent an exciting therapeutic strategy for acute liver injury; however, the authors note the need for additional in vitro and in vivo research to strengthen their claim and bring this potential effective treatment approach a step closer to the clinic. Future research directions include an assessment of the repopulation potential of engineered liver epithelial progenitor cells and an evaluation of their ability to replace the function of the injured liver.

For more on engineered liver progenitors as a potentially safe and effective treatment for acute liver injury, stay tuned to the Stem Cells Portal!

References

1. Li W-L, Su J, Yao Y-C, et al., Isolation and Characterization of Bipotent Liver Progenitor Cells from Adult Mouse. STEM CELLS 2006;24:322-332.
2. Zheng JF, Liang LJ, Wu CX, et al., Transplantation of fetal liver epithelial progenitor cells ameliorates experimental liver fibrosis in mice. World Journal of Gastroenterology 2006;12:7292-8.
3. Abe Y, Uchinami H, Kudoh K, et al., Liver epithelial cells proliferate under hypoxia and protect the liver from ischemic injury via expression of HIF-1 alpha target genes. Surgery 2012;152:869-878.
4. Shi X-L, Gao Y, Yan Y, et al., Improved survival of porcine acute liver failure by a bioartificial liver device implanted with induced human functional hepatocytes. Cell Research 2016;26:206-216.
5. Ullah I, Subbarao Raghavendra B, and Rho Gyu J, Human mesenchymal stem cells - current trends and future prospective. Bioscience Reports 2015;35.
6. LaBrecque DR and Pesch LA, Preparation and partial characterization of hepatic regenerative stimulator substance (SS) from rat liver. The Journal of Physiology 1975;248:273-284.
7. Thirunavukkarasu C, Wang LF, Harvey SAK, et al., Augmenter of liver regeneration: An important intracellular survival factor for hepatocytes. Journal of Hepatology 2008;48:578-588.
8. Jiang S-J, Li W, and An W, Adenoviral Gene Transfer of Hepatic Stimulator Substance Confers Resistance Against Hepatic Ischemia-Reperfusion Injury by Improving Mitochondrial Function. Human Gene Therapy 2013;24:443-456.
9. Nalesnik MA, Gandhi CR, and Starzl TE, Augmenter of liver regeneration: A fundamental life protein. Hepatology 2017;66:266-270.
10. Dong Y, Kong W, and An W, Downregulation of augmenter of liver regeneration impairs the therapeutic efficacy of liver epithelial progenitor cells against acute liver injury by enhancing mitochondrial fission. STEM CELLS 2021;39:1546-1562.