Z Gastroenterol 2011; 49 - P3_25
DOI: 10.1055/s-0030-1269640

Activin A resistant fetal liver stem/progenitor cells (FLSPC) vigorously repopulate aging rat liver through augmented cell competition

A Menthena 1, CI Koehler 1, JS Sandhu 1, MI Yovchev 1, E Hurston 1, DA Shafritz 1, M Oertel 1
  • 1Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, USA

Recently, we showed that highly proliferative FLSPC repopulate the normal young recipient liver by out-competing less proliferative host hepatocytes (HC) by inducing their apoptosis. The aim of the study was to discover the mechanism through which FLSPC are capable to repopulate the recipient liver and more effectively repopulate the liver of aging rats.

We observed a 4–5fold increase of liver repopulation after FLSPC transplantation into rats of advancing age. In aging liver, mRNA expression of cyclin-dependent kinase inhibitors increased progressively, most notably p15INK4b, a gene recently reported to be a de novo marker for senescence. Isolated 20 mo. old HC exhibited a 6fold higher p15INK4b expression and a 3fold reduced proliferative activity in vitro compared to HC from 2 mo. old rats.

Expression of p15INK4b in differentiated HC is upregulated by activin A, which also increases progressively in aging rat liver. In vitro studies showed that adult HC are clearly growth-inhibited by activin A. However, activin A showed no effect on proliferation of FLSPC, because these cells exhibit reduced expression of activin receptors (ActR-IIA, -IIB, ALK-4).

Lastly, using laser capture microdissection, transplanted FLSPC that had expanded into cell clusters in aging liver showed much lower levels of ALK-4 and p15INK4b and increased Ki-67 expression compared to surrounding host parenchyma, in which the numbers of apoptotic cells were 3fold higher in older compared to younger rats.

In summary, FLSPC, which have a growth advantage through their resistance to activin A-induced growth inhibition, vigorously repopulate the (aging) host liver, which is impaired in regenerative capacity by endogenous activin A, leading to increased cell competition between transplanted FLSPC and host HC. Therefore, patients with liver diseases in which increased activin A levels have been observed might be good candidates for cell transplantation strategies based on cell competition.