Autophagy-mediated regulation of hepatic differentiation of human adipose tissue-derived mesenchymal stem cells

Apr 9, 2026The international journal of biochemistry & cell biology

How Cell Recycling Controls Liver-Like Development of Human Fat-Derived Stem Cells

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Abstract

Autophagy activation was observed during baseline differentiation of adipose tissue-derived mesenchymal stem cells into hepatocyte-like cells over 21 days.

Autophagy-related markers Beclin-1, LC3B, and ATG7 increased, while p62 decreased during differentiation.
Morphological changes consistent with hepatocyte-like cells were confirmed through transmission electron microscopy and acridine orange staining.
Induction of autophagy via serum starvation or rapamycin treatment enhanced hepatic functional markers, including elevated secreted albumin and urea levels.
Inhibition of autophagy using 3-methyladenine impaired hepatic functional characteristics in differentiated cells.
These findings suggest that autophagy may play a regulatory role in the differentiation of mesenchymal stem cells into hepatocyte-like cells.

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The regulation of mesenchymal stem cell (MSC) differentiation is a complex process influenced by multiple factors, among which autophagy has emerged as a key determinant of stem cell fate. Here, we investigated its role in MSC differentiation into hepatocyte-like cells. Autophagy was first assessed during basal hepatic differentiation of adipose tissue-derived MSCs (AD-MSCs) in the absence of modulators. Subsequently, we evaluated the impact of autophagy modulation by chemical agents on the functionality of the derived hepatocyte-like cells. Isolated AD-MSCs were induced to differentiate, and hepatocyte formation was assessed by morphological, molecular, and biochemical analyses. Macroautophagy was examined via protein and mRNA expression of key autophagy‑related markers, supplemented with transmission electron microscopy (TEM) and acridine orange staining. To confirm the role of autophagy in hepatic differentiation, differentiating MSCs were subjected to autophagy induction by serum starvation or treatment with rapamycin (50nM), and inhibition using 3‑methyladenine (3‑MA, 5µM). Autophagy activation was observed during baseline differentiation (days 0, 7, 14, and 21 post-induction), as indicated by increased Beclin‑1, LC3B, and ATG7 expression; reduced p62; and accumulation of autophagic vacuoles confirmed by TEM and acridine orange staining. Induction of autophagy by rapamycin or serum starvation enhanced hepatic functional markers, as evidenced by higher levels of secreted albumin and urea, along with increased ALT and AST activities, whereas 3‑MA impaired these parameters. Collectively, these findings indicate that autophagy supports the acquisition of hepatic functional and metabolic characteristics in MSC‑derived hepatocyte-like cells, providing insight into its regulatory role during MSC differentiation toward hepatocyte-like cells.

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Autophagy-mediated regulation of hepatic differentiation of human adipose tissue-derived mesenchymal stem cells

Abstract

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