Pharmacological Mobilization of Endogenous Bone Marrow Stem Cells Promotes Liver Regeneration after Extensive Liver Resection in Rats

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.

Perspectives of pharmacological intervention promoting liver regeneration

“…Engraftment of CD133 + stem cells in the remnant liver and increased proliferation of hepatic double-stained OV6/Ki67 oval cells was obtained in animals pretreated with combination of two drugs: AMD3100 (Plerixafor or Mozobil) and low dose of FK506 immunosup-pressant. Thus synergistic action of these two drugs resulted in mobilization and recruitment of bone marrow stem cells [10].…”

“…For this reason, the pharmacological activation of endogenous stem cells could be a simple and effective method of presenting stem cells to injured liver. In rat model, pharmacological mobilization of bone marrow cells promoting liver regeneration was recently evidenced after extensive liver resection [10]. Engraftment of CD133 + stem cells in the remnant liver and increased proliferation of hepatic double-stained OV6/Ki67 oval cells was obtained in animals pretreated with combination of two drugs: AMD3100 (Plerixafor or Mozobil) and low dose of FK506 immunosup-pressant.…”

“…Bone-marrow-derived cells were found in the liver of healthy animals [6], as well as in regenerating liver after PH [9]. Thus liver regeneration may not only depend on proliferation of intact hepatocytes and local stem cells, but also can be related to migration of stem cells and macrophages from bone marrow [10,11]. Thus in animal models, depending the cause and severity of injury, liver regeneration was divided into three distinct restoring levels: hepatocyte dominant regeneration, participation of liver stem/progenitor cells, and involvement of extrahepatic stem/progenitor cells [6].…”

Liver regeneration in traditional Chinese medicine: advances and challenges

“…For the alternative regeneration mechanism, bloodborne cells of the bone marrow origin also play a role, in addition to the resident liver cells [11][12][13]. Hepatic stellate cells (HSCs) are also an important element of the liver regeneration machinery being part of liver stem cell niche, supporting regeneration at early stages by producing growth factors and inducing regeneration arrest after restoration of normal organ mass [14].…”

Hepatic progenitor cell activation is induced by the depletion of the gut microbiome in mice

“…The source of HPCs remains controversial. Some researchers contend that these cells exist in a quiescent state around bile ducts until activated (Tee, Kirilak, Huang, Morgan, & Yeoh, ; Tee, Smith, & Yeoh, ), while other researchers contend that some HPCs originate from hepatocytes (Wu & Lee, ) or from an extrahepatic source, especially bone marrow (Li et al, ; Zhai et al, ). In addition, recent studies have indicated that HPCs originate from the transdifferentiation of biliary epithelial cells (Raven et al, ).…”