Inhibition of the RhoGTPase Cdc42 by ML141 enhances hepatocyte differentiation from human adipose-derived mesenchymal stem cells via the Wnt5a/PI3K/miR-122 pathway: impact of the age of the donor.

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Background Human adipose-derived mesenchymal stem cells (hADSCs) are promising cells that may promote hepatocyte differentiation (Hep-Dif) and improve liver function, but the involvement of Cdc42, a key small RhoGTPase which plays a crucial role in aging, is still not well established. We hypothesized that the inhibition of Cdc42 may rescue the hepatogenic potential of hADSCs derived from aged donors. Methods hADSCs isolated from 61 women of different ages were cultured for evaluation of the proliferation of cells, adherence, apoptosis, immunomodulation, immunophenotyping, multipotency, gene expression, and cell function during Hep-Dif. Inhibition of Cdc42 by ML141 was realized during two phases: initiation (days -2 to 14 (D-2/14)) from undifferentiated to hepatoblast-like cells, or maturation (days 14 to 28 (D14/28)) from undifferentiated to hepatocyte-like cells. Mechanistic insights of the Wnt(s)/MAPK/PI3K/miR-122 pathways were studied. Results Cdc42 activity in undifferentiated hADSCs showed an age-dependent significant increase in Cdc42-GTP correlated to a decrease in Cdc42GAP; the low potentials of cell proliferation, doubling, adherence, and immunomodulatory ability (proinflammatory over anti-inflammatory) contrary to the apoptotic index of the aged group were significantly reversed by ML141. Aged donor cells showed a decreased potential for Hep-Dif which was rescued by

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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