Boston, MA -
The ability of stem cells to inhibit progression of liver disease has been demonstrated in pilot human clinical trials. However the mechanisms by which bone marrow stem cell populations mediate antifibrotic effects are not completely known. In the mentioned clinical trial, administration of intravenous autologous bone marrow stem cells was associated with increased proliferation in the liver as detected by proliferating cell nuclear antigen (PCNA) staining. This is an effect but not a cause of regeneration.
This question was addressed by a recent paper (Parekkadan et al. Immunomodulation of activated hepatic stellate cells by mesenchymal stem cells. Biochem Biophys Res Commun. 2007 Nov 16;363(2):247-52).
The investigators were interested in the interaction between the mesenchymal stem cells and the stellate cell. The stellate cell of the liver (also called Ito cells) are involved in causing liver fibrosis, that is, overgrowth of scar tissue resulting in replacement of functional liver tissue. Stellate cells normal store fat and reside in the area between the sinusoids and hepatocytes, called the "perisinusoidal space". Immunological roles of stellate cells has been proposed in that these cells can activate NKT cells in a CD1 dependent manner (Winau et al. Ito cells are liver-resident antigen-presenting cells for activating T cell responses. Immunity. 2007 Jan;26(1):117-29).
The investigators noticed that if one co-cultures stellate cells with mesenchymal stem cells, then the stellate cells reduce ability do produce collagen. Additionally, mesenchymal stem cells appeared to specifically induce apoptosis of activated, but not quiescent stellate cells.
It was found that activated stellate cells produce IL-6. The IL-6 then induced mesenchymal stem cells to produce IL-10. The IL-10 made by the mesenchymal stem cells suppressed proliferation of activated stellate cells, as well as suppressed their ability to produce collagen.
Induction of apoptosis of activated stellate cells by mesenchymal stem cells seems to have been caused by hepatocyte growth factor produced by the activated mesenchymal stem cells.
The identification of mesenchymal stem cell produced signals that inhibit cirrhosis, at least at the cellular level, will play an important role in determining optimum types of mesenchymal stem cells for use in treatment of this deadly disease.