Contribution of human hematopoietic stem cells to liver repair

Abstract

Immune-deficient mouse models of liver damage allow examination of human stem cell migration to sites of damage and subsequent contribution to repair and survival. In our studies, in the absence of a selective advantage, transplanted human stem cells from adult sources did not robustly become hepatocytes, although some level of fusion or hepatic differentiation was documented. However, injected stem cells did home to the injured liver tissue and release paracrine factors that hastened endogenous repair and enhanced survival. There were significantly higher levels of survival in mice with a toxic liver insult that had been transplanted with human stem cells but not in those transplanted with committed progenitors. Transplantation of autologous adult stem cells without conditioning is a relatively safe therapy. Adult stem cells are known to secrete bioactive factors that suppress the local immune system, inhibit fibrosis (scar formation) and apoptosis, enhance angiogenesis, and stimulate recruitment, retention, mitosis, and differentiation of tissue-residing stem cells. These paracrine effects are distinct from the direct differentiation of stem cells to repair tissue. In patients at high risk while waiting for a liver transplant, autologous stem cell therapy could be considered, as it could delay the decline in liver function.

Fig. 1

FISH analysis for human and mouse centromeres in liver sections. Liver sections from a mouse that had been transplanted with ALDH^hiLin⁻ cells after CCL4-mediated liver injury were probed with both human (red dots in nuclei) and mouse (green dots in nuclei) centromeric probes. The analysis shows that the liver was heavily engrafted with human stem cells and that the majority of the human cells had not undergone fusion with the damaged murine hepatocytes

Fig. 2

MPSVII liver. Engraftment of human ALDH^hiLin⁻ cells into mouse livers. Representative frozen section slides from the livers of mice transplanted with human cord blood ALDH^loLin⁻ (left) or ALDH^hiLin⁻ cells (right). Liver sections were stained for β-glucuronidase (red) and counterstained for methyl green (green nuclei)