Mesenchymal stem cells alleviate mouse liver fibrosis by inhibiting pathogenic function of intrahepatic B cells

Background & aims:The immunomodulatory characteristics of mesenchymal stem cells (MSCs) make them a promising therapeutic approach for liver fibrosis (LF). Here, we postulated that MSCs could potentially suppress the pro-fibrotic activity of intrahepatic B cells, thereby inhibiting LF progression. Approach & results:Administration of MSCs significantly ameliorated LF as indicated by reduced myofibroblast activation, collagen deposition, and inflammation. The treatment efficacy of MSCs can be attributed to decreased infiltration, activation, and pro-inflammatory cytokine production of intrahepatic B cells. Single-cell RNA sequencing revealed a distinct intrahepatic B cell atlas and a subtype of naive B cells (B-II) was identified, which were markedly abundant in fibrotic liver, displaying mature features with elevated expression of several proliferative and inflammatory genes. Transcriptional profiling of total B cells revealed that intrahepatic B cells displayed activation, proliferation, and pro-inflammatory gene profile during LF. Fibrosis was attenuated in mice ablated with B cells (mu MT) or in vivo treatment with anti-CD20. Moreover, fibrosis was recapitulated in mu MT after adoptive transfer of B cells, which in turn could be rescued by MSC injection, validating the pathogenic function of B cells and the efficacy of MSCs on B cell-promoted LF progression. Mechanistically, MSCs could inhibit the proliferation and cytokine production of intrahepatic B cells through exosomes, regulating the MAPK and NF-kappa B signaling pathways. Conclusions: Intrahepatic B-cell serve as a target of MSCs, play an important role in the process of MSC-induced amelioration of LF, and may provide new clues for revealing the novel mechanisms of MSC action.