BackgroundSmall hepatocyte-like progenitor cells (SHPCs) are hepatocytic progenitor cells that transiently form clusters in rat livers treated with retrorsine (Ret) that underwent 70% partial hepatectomy (PH). We previously reported that transplantation of Thy1+cells obtained fromd-galactosamine-treated livers promotes SHPC expansion, thereby accelerating liver regeneration. Extracellular vesicles (EVs) secreted by Thy1+cells induce sinusoidal endothelial cells (SECs) and Kupffer cells (KCs) to secrete IL17B and IL25, respectively, thereby activating SHPCs through IL17 receptor B (RB) signaling. This study aimed to identify the inducers of IL17RB signaling and growth factors for SHPC proliferation in EVs secreted by Thy1+cells (Thy1-EVs).MethodsThy1+cells isolated from the livers of rats treated withd-galactosamine were cultured. Although some liver stem/progenitor cells (LSPCs) proliferated to form colonies, others remained as mesenchymal cells (MCs). Thy1-MCs or Thy1-LSPCs were transplanted into Ret/PH-treated livers to examine their effects on SHPCs. EVs were isolated from the conditioned medium (CM) of Thy1-MCs and Thy1-LSPCs. Small hepatocytes (SHs) isolated from adult rat livers were used to identify factors regulating cell growth in Thy1-EVs.ResultsThe size of SHPC clusters transplanted with Thy1-MCs was significantly larger than that of SHPC clusters transplanted with Thy1-LSPCs (p= 0.02). A comprehensive analysis of Thy1-MC-EVs revealed thatmiR-199a-5p, cytokine-induced neutrophil chemoattractant-2 (CINC-2), and monocyte chemotactic protein 1 (MCP-1) were candidates for promoting SHPC growth. Additionally,miR-199a-5pmimics promoted the growth of SHs (p= 0.02), whereas CINC-2 and MCP-1 did not. SECs treated with CINC-2 inducedIl17bexpression. KCs treated with Thy1-EVs induced the expression of CINC-2,Il25, andmiR-199a-5p. CM derived from SECs treated with CINC-2 accelerated the growth of SHs (p= 0.03). Similarly, CM derived from KCs treated with Thy1-EVs andmiR-199a-5pmimics accelerated the growth of SHs (p= 0.007). In addition, althoughmiR-199a-overexpressing EVs could not enhance SHPC proliferation, transplantation ofmiR-199a-overexpressing Thy1-MCs could promote the expansion of SHPC clusters.ConclusionThy1-MC transplantation may accelerate liver regeneration owing to SHPC expansion, which is induced by CINC-2/IL17RB signaling andmiR-199a-5pvia SEC and KC activation.Graphical AbstractSupplementary InformationThe online version contains supplementary material available at 10.1186/s13287-023-03346-z.