Early loss of bone marrow hematopoietic stem cells drives regeneration failure in cirrhosis

Liver failure is failure of regeneration. Underlying cause of regeneration failure in cirrhosis is not well-defined. Bone marrow stem cells (BMSC) and their progeny play a central role in tissue repair and regeneration and are defective in patients with chronic liver failure. Whether BM failure is cause or consequence of liver failure in cirrhosis is not known. In this study we aim to decipher the underlying relation between BM failure and regeneration failure in cirrhosis. Using murine model of chronic liver injury we showed that loss of BMSC occurs prior to failure of liver regeneration and onset of non-acute decompensation. We further showed, infusion of healthy-BM in cirrhotic-BM dampens the inflammation, increase glycolysis and induce the repopulation of native LT-HSCs. Restoring LT-HSCs reserve in cirrhotic animals restore liver macrophage number and function, accelerate regression of fibrosis, enhanced liver regeneration and delay the onset of non-acute decompensation. It improved liver clearance of immune complex, dampens neutrophil-mediated inflammation and shifted energy metabolism from glycolysis to OXPHOS. Therefore, early loss of BMSC reserve compromise innate immune function of liver and drive the regeneration failure in cirrhosis. We also provide the proof-of-concept that rejuvenating BM-HSC reserve as putative therapeutic approach to prevent regeneration failure in cirrhosis.