Abstract
Rapid regeneration of the remnant liver is critical for preventing liver failure and promoting recovery after extensive liver resection. Numerous studies have demonstrated the involvement of bone marrow-derived stem cells in liver regeneration and the potential benefits of bone marrow stem cell therapy. To avoid the preparation of stem cells, we proposed in this study to mobilize endogenous bone marrow stem cells pharmacologically with a combination of AMD3100 (A), an antagonist of CXCR4 and low-dose FK506 (F). Here we show that AF combination therapy significantly increased lineage negative (Lin-) CD34+ and Lin-CD133+ stem cells in peripheral blood and enhanced recruitment of CD133+ cells into the remnant liver in a rat model of 85% partial hepatectomy. Recruiting CD133+ stem cells in the remnant liver was associated with increased proliferation of hepatic oval cells and paralleled the increased SDF-1, CXCR4 and HGF expression. Importantly, AF combination therapy increased the number of Ki67 positive hepatocytes and BrdU incorporation in the remnant liver and improved serum levels of albumin. Our results demonstrate that pharmacological mobilization of endogenous bone marrow stem cells with AF combination therapy can enhance endogenous stem cell mobilization to promote liver regeneration and improve liver function after extensive hepatectomy.
Highlights
Liver regeneration after partial hepatectomy depends on the proliferation of hepatocytes
Pharmacological mobilization of bone marrow stem cells with AF combination therapy improves liver function in rats after extensive liver resection. 85% partial hepatectomy was performed in rats by ligating vascular structures within the liver parenchyma separately (Fig. 1a) and only the right superior lobe (RSL) was retained (Fig. 1b)
All rats survived after 85% partial hepatectomy and this survival was associated with mobilization of lineage negative (Lin-)CD34+ and Lin-CD133+ bone marrow stem cells in circulation and engraftment of CD133+ stem cells in the remnant liver, but decreased levels of serum albumin
Summary
Liver regeneration after partial hepatectomy depends on the proliferation of hepatocytes. Recruitment of BM progenitors of LSECs to the hepatic sinusoid after partial hepatectomy is required for normal liver regeneration[17] These findings led to studies using BM-derived HSCs or MSCs. HSCs and MSCs were shown to undergo hepatogenic differentiation and to populate liver after intravenous transplantation in rat, mouse and pig models www.nature.com/scientificreports/. One week of AF combination treatment plus repeat dosing at 1, 2 and 3 months resulted in immunosuppressive drug-free long term kidney allograft survival in rats[25] and in maximally immunologically mismatched swine[26]. These results will assist in the development of a therapeutic strategy for liver failure
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