A novel role of angiotensin II in epidermal cell lineage determination: Angiotensin II promotes the differentiation of mesenchymal stem cells into keratinocytes through the p38 MAPK, JNK and JAK2 signalling pathways.

BACKGROUND:Recent evidence suggests that angiotensin II (Ang II) plays a role in cutaneous wound healing. Mesenchymal stem cells (MSCs) are known as a rich source of cells that re-establish healed skin. However, the potential impact of Ang II on MSC differentiation into keratinocytes is still unknown. OBJECTIVE:The present study was conducted to explore the effect of Ang II on the differentiation of bone marrow-derived MSCs (BM-MSCs) into keratinocytes. METHODS:Bone marrow-derived MSCs were isolated from rat bone marrow and cultured. The expression of Ang II type 1 (AT₁ ) and type 2 (AT₂ ) receptors was examined by immunofluorescence staining. The differentiation of BM-MSCs into keratinocytes was investigated by flow cytometry or/and histological observation. RESULTS:The BM-MSCs constitutively expressed both AT₁ and AT₂ receptors. The differentiation of BM-MSCs into keratinocytes was successfully induced. Interestingly, incubation of BM-MSCs with Ang II further promoted the differentiation of BM-MSCs into keratinocyte, which was abolished by pretreament with losartan, an AT₁ receptor antagonist, but not by PD123319, an AT₂ receptor antagonist. Moreover, the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580, the c-Jun N-terminal kinase (JNK) inhibitor SP600125 and the Janus-activated kinase (JAK)2 inhibitor AG490 suppressed Ang II-induced differentiation of BM-MSCs into keratinocytes. The phosphoinositide-3 kinase (PI3K) inhibitor wortmannin and MEK1/2 inhibitor U0126 had no effect on BM-MSC differentiation into keratinocytes. CONCLUSIONS:Our data demonstrated for the first time that Ang II plays a promotive role in the differentiation of BM-MSC into keratinocytes through the AT₁ receptor, and that the p38 MAPK, JNK and JAK2 signalling pathways are involved in this process.

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