In rodents and humans, the liver can efficiently restore its mass after hepatectomy. This is largely attributed to the proliferation and cell cycle re-entry of hepatocytes. On the other hand, bone marrow cells (BMCs) migrate into the liver after resection. Here, we find that a block of BMC recruitment into the liver severely impairs its regeneration after the surgery. Mobilized hematopoietic stem and progenitor cells (HSPCs) in the resected liver can fuse with hepatocytes, and the hybrids proliferate earlier than the hepatocytes. Genetic ablation of the hybrids severely impairs hepatocyte proliferation and liver mass regeneration. Mathematical modeling reveals a key role of bone marrow (BM)-derived hybrids to drive proliferation in the regeneration process, and predicts regeneration efficiency in experimentally non-testable conditions. In conclusion, BM-derived hybrids are essential to trigger efficient liver regeneration after hepatectomy.

This work was supported by an ERC grant (242630-RERE to M.P.C.), the Ministerio de Economia y Competitividad and FEDER funds (SAF2011-28580, BFU2014-54717-P, and BFU2015-71984-ERC to M.P.C.), an AGAUR grant from Secretaria d'Universitats i Investigació del Departament d'Economia i Coneixement de la Generalitat de Catalunya (2014SGR1137 to M.P.C.), an MRC grant (MR/N021444/1 to L.M.), BrisSynBio, BBSRC/EPSRC Synthetic Biology Research Centre (BB/L01386X/1 to L.M.), and Engineering and Physical Sciences Research Council (EP/I013717/1 to V.A.O.). We acknowledge support of the Spanish Ministry of Economy and Competitiveness, Centro de Excelencia Severo Ochoa 2013-2017 and of the CERCA Programme/Generalitat de Catalunya.