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Mesenchymal stem cells (MSCs) have great potential for cell therapy in regenerative medicine, including liver disease. Even though ongoing research is dedicated to the goal of bringing MSCs to clinical applications, further understanding of the complex underlying mechanisms is required. Autophagy, a type II programmed cell death, controls cellular recycling through the lysosomal system in damaged cells or tissues. However, it is still unknown whether MSCs can trigger autophagy to enhance regeneration and/or to provide a therapeutic effect as cellular survival promoters. We therefore investigated autophagy's activation in carbon tetrachloride (CCl 4 )‐injured rat liver following transplantation with chorionic plate‐derived MSCs (CP‐MSCs) isolated from placenta. The expression markers for apoptosis, autophagy, cell survival, and liver regeneration were analyzed. Whereas caspase 3/7 activities were reduced ( p  &lt; .05), the expression levels of hypoxia‐inducible factor‐1α (HIF‐1α) and factors for autophagy, survival, and regeneration were significantly increased by CP‐MSCs transplantation. Decreased necrotic cells ( p  &lt; .05) and increased autophagic signals ( p  &lt; .005) were observed in CCl 4 ‐treated primary rat hepatocytes during in vitro coculture with CP‐MSCs. Furthermore, the upregulation of HIF‐1α promotes the regeneration of damaged hepatic cells through an autophagic mechanism marked by increased levels of light chain 3 II (LC 3II). These results suggest that the administration of CP‐MSCs promotes repair by systemically concomitant mechanisms involving HIF‐1α and autophagy. These findings provide further understanding of the mechanisms involved in these processes and will help develop new cell‐based therapeutic strategies for regenerative medicine in liver disease. S TEM  C ells  2013;31:1584–1596

Human Placenta‐Derived Mesenchymal Stem Cells Promote Hepatic Regeneration in CCl 4 ‐Injured Rat Liver Model via Increased Autophagic Mechanism