Modeling Dynamics and Function of Bone Marrow Cells in Mouse Liver Regeneration

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. [Display omitted] •Bone marrow cell migration after liver hepatectomy is key for liver regeneration•Migrated bone marrow cells fuse with hepatocytes•Hybrids are essential for liver regeneration•Mathematical modeling unveils the hybrid function for liver regeneration Hepatocyte replication is considered the main mechanism of liver regeneration after hepatectomy in mammals. Pedone et al. report that bone marrow cells can migrate into the liver upon resection and fuse with the hepatocytes. The derived hybrids are essential for efficient liver regeneration, which is also predicted by mathematical modeling.