MSC transplantation exerts restorative effects in liver disease models, including acute plus chronic liver failure. Additionally , MSC transplantation has been shown to enhance the liver microenvironment, mediating restoration of liver perform, reduction of inflammation, and augmentation of liver reconstruction [ 32 ]. In our study, paracrine signaling from MSCs can induce the formation of hepatic oval tissues via secretary exosomes. These findings could clarify the particular involvement of MSCs in therapies for liver illnesses.

During liver organ regeneration, it is reported that the expression of neonatal guns, alpha fetoprotein and EpCAM, is upregulated [ 18 , 33 ]. EpCAM is a marker of intrahepatic stem cells which usually present in normal and injured liver [ 18 ]. Additionally , EpCAM is reported to express in undifferentiated stem tissue and progenitors in development of organs, and drop to some very low level with terminal differentiation [ 34 , 35 ]. Throughout liver development of mice, EpCAM was expressed in liver organ buds as early as E9. 5, decreased to low-level appearance in hepatoblasts of E13. 5, and not expressed whenever cells are switched onto specification to the hepatic destiny [ 36 ]. The dynamic expression of EpCAM can also be considered to correlate with plasticity of hepatocyte [ 37 ]. In addition , alpha fetoprotein and cytokeratin 19 are extremely expressed in hepatic oval cells, which proliferate within the early stage of liver regeneration [ 25 , 38 ]. Along, the above evidence supports the conversion of hepatocytes in to hepatic progenitor cells.

Exosomes play an important role in cell-to-cell conversation [ 9 , 39 ]. By the transport system of exosomes, miRNAs are usually packaged and trafficked to recipient cells [ 40 ]. Moreover, many reports indicate that exosomal miRNAs may manipulate gene expression, and stimulate angiogenesis and immigration in neighboring cells [ 41 43 ]. These secreted miRNAs can function as endogenous miRNAs to affect translation plus manipulate cell signaling in recipient cells. Variety of miRNAs in exosomes are recorded in the ExoCarta database [ 44 ]. Although we found that MSC-secreted exosomes can induce formation of hepatic oval cells, further research are needed to investigate which candidates of MSC exosomal miRNAs are involved in the formation of hepatic oval cells. Within our study, not all of the hepatocytes were altered to EpCAM high small oval cells along with MSC-CM treatment, which may imply efficiency of exosome engulfing in hepatocytes and other important unknown key factors released from MSCs.

MSC-secreted growth factors and cytokines [ 4 , 7 ] may also be involved in the process of liver regeneration. Hepatocyte growth element (HGF) is an important growth factor to participate in liver revitalization [ 45 ]. In the early stage of liver reconstruction, HGF expression is rapidly elevated from 3 in order to 48  hours and acts as an initiator of liver organ regeneration [ 46 ]. Also, genetic deletion of c-Met blocks liver regeneration and impairs liver functions, demonstrating that HGF/c-Met signaling is essential for liver regeneration [ 47 , 48 ]. In addition , proteomics analysis also shows abundant HGF within MSC-derived exosomes [ 49 ]. Therefore , further investigation is needed on whether HGF/c-Met signaling is involved in hepatocyte dedifferentiation.

In the research, CD26 + hepatocytes were transformed into small oval cells with higher EpCAM expression right after treatment of concentrated MSC-secreted exosomes. Although the phenomenon was seen in the MSC-CM treatment, other factors which were not packaged to the exosomes could also be involved in the conversion of CD26 + hepatocytes to small oval cells along with higher EpCAM expression. Also, another study analyzed the and intersection of the proteomic profile between MSC-CM plus MSC-derived exosomes [ 49 ]. Therefore , the effectiveness of inducing hepatocyte dedifferentiation will need to be compared and investigated among MSC-CM, MSC-derived exosomes, and exosome-free MSC-CM. Furthermore, the key factors plus regulators also need to be further elucidated.

By lineage tracing, hepatocytes may dedifferentiate to hepatic progenitor cells and then replenish hepatocytes in liver regeneration [ 20 ]. Also, there is several evidence indicating the increase of alpha fetoprotein appearance, a marker of hepatic oval cells, after MSC transplantation in animal models [ 50 , 51 ]. However , it really is still unclear whether MSC transplantation can induce or even increase the formation of hepatic oval cells in vivo. In the study, we demonstrated that paracrine signaling through MSCs can induce the formation of hepatic oblong cells in vitro, and further investigation will be performed within future studies on whether MSCs transplantation and management of MSC-CM and MSC-derived exosomes can induce receiver hepatocytes into hepatic oval cells in vivo.

MSC transplantation will be thought to be quite safe, and many clinical trials have been performed within the last decade [ 52 , 53 ]. However , there are some concerns concerning the potential for tumorigenesis owing to the development of chromosomal aberrations in cellular culture [ 54 56 ]. Alternatively, stem cell-derived molecules within CM, including cytokines, growth factors, and exosomes, can offer a more safe treatment method without cell transplantation. Therefore , evaluation of the paracrine effects of MSCs may provide more achievable treatment guidelines in clinical applications.