Nerve growth factor-mediated paracrine regulation of hepatic stellate cells by multipotent mesenchymal stromal cells

Multipotent mesenchymal stromal cells (MSC) have been reported to prevent the development of liver fibrosis and have emerged as a promising strategy for cell-based therapy. However, the underlying therapeutic mechanism remains unclear. Hepatic stellate cells (SC) activation is a pivotal event in the development of liver fibrosis. We hypothesized that MSC play an important role in regulating SC proliferation and apoptosis through paracrine mechanisms. To investigate the paracrine interactions between MSC and SC, a co-culture experimental model was developed using human MSC (hMSC) and human SC (hSC). We demonstrate that hMSC and hSC both express nerve growth factor (NGF) receptor p75. Results acquired from transwell co-culture experiments using hSC and hMSC showed that hMSC secrete NGF, which enhances hSC apoptosis. Transcription factor nuclear factor kappa B (NF-ΚB) and B cell leukemia-xl (Bcl-xl) take part in the process. These findings demonstrated that hMSC indirectly modulate activated hSC in vitro via NGF-mediated signaling cascades and provide a potential mechanism of how transplanted MSC are effective in treating liver fibrosis.