Basic studies for the development of efficient liver regenerative therapy using bone marrow cells

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We have developed an in vivo mouse model, the GFP/CC14 model, and have reported that transplanted GFP-positive bone marrow cells (BMCs) differentiate into hepatocytes and improve /CC14-induced cirrhosis. We have also reported that fibroblast growth factor 2 (FGF2) facilitated the differentiation of transplanted BMCs into hepatocytes. However, it is unclear the mechanism(s) of the differentiation from transplanted BMCs into hepatocytes. In 2006, our studies demonstrated that administration of FGF2 in combination with bone marrow transplantation (BMT) synergistically activated tumor necrosis factor-alpha signaling and significantly improved liver function and prognosis more than BMC infusion alone, suggesting that FGF2 had an important role in liver regeneration. Next, in 2007, we analyzed why the injected BMC are resistant to /CC14 damage and subsequently improve the local microenvironment in damaged liver. To analyze the cellular phenomena involved in this process, we studied the damag … More ed liver using electron microscopy. We found that /CC14 caused rough endoplasmic reticule to swell in hepatocytes. To analyze the gene expression patterns associated with this process, we conducted PCR-selected suppressive subtractive hybridization. We found that expression levels of HSP84, HSP40, and XBPI differed markedly between control liver and liver infused with BMC. Immunohistochemical staining revealed that expression levels of HSP84 and HSP40 were markedly higher in the early phase of differentiation immediately after BMC infusion, but decreased over time. XBPI expression remained high during the late phase, and GRP78 expression increased with XBPI activation. We also found that GFP-positive BMC expressed XBPI and GRP78. XBP1 and GRP78 are associated with ER stress. Thus, continuous high XBPI and GRP78 expression might be essential for the survival and proliferation of BMC in a CC14-induced persistent liver damage environment. These basic studies are important for the development of an effective autologous bone marrow cell infusion (ABMI) therapy for patients with liver cirrhosis. Less