Stem Cells. 2017 Feb 16. doi: 10.1002/stem.2593. [Epub ahead of print]

Effects of human mesenchymal stem cells co-culture on calcium-induced differentiation of normal human keratinocytes.

Sah SK¹, Kim HY¹, Lee JH², Lee SW³, Kim HS⁴, Kim YS⁵, Kang KS⁶, Kim TY¹.

Abstract

The influence of mesenchymal stem cells (MSCs) on keratinocytes in altered microenvironments is poorly understood. Here, we co-cultured umbilical cord blood-derived MSCs with normal human epidermal keratinocytes (NHEK) to evaluate their paracrine effect in the presence of high extracellular calcium (Ca²⁺ ) concentration. High Ca²⁺ environment to keratinocytes can disrupt normal skin barrier function due to abnormal/premature differentiation of keratinocytes. Surprisingly, we found that MSCs suppress both proliferation and differentiation of keratinocytes under a high Ca²⁺ environment in TGFβ1-dependent manner. Furthermore, we determined that MSCs can regulate the mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), and protein kinase C (PKCα) pathways in Ca²⁺ -induced differentiated keratinocytes. Knockdown of TGFβ1 from MSCs results in decreased suppression of differentiation with significantly increased proliferation of keratinocytes compared with control MSCs. MSCs-derived TGFβ1 further induced growth inhibition of keratinocyte in high extracellular Ca²⁺ environment as analyzed by a decrease in DNA synthesis, accumulation of phosphorylated retinoblastoma protein (pRb), cdc2, and increased mRNA level of p21, and independent of TGFβ1/SMAD pathway. Taken together, we found that MSCs-derived TGFβ1 is a critical regulator of keratinocyte function, and involves multiple proximal signaling cascades. This article is protected by copyright. All rights reserved.