Sah Shyam Kishor, Kim Hae Young, Lee Ji Hae, Lee Seong-Wook, Kim Hyung-Sik, Kim Yeon-Soo, Kang Kyung-Sun, Kim Tae-Yoon
Laboratory of Dermatology-Immunology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Department of Dermatology, The Catholic University of Korea, St. Vincent's Hospital, Jungbu-daero, Paldal-gu, Suwon-si, Gyeonggi-do, Republic of Korea.
Stem Cells. 2017 Jun;35(6):1592-1602. doi: 10.1002/stem.2593. Epub 2017 Mar 14.
The influence of mesenchymal stem cells (MSCs) on keratinocytes in altered microenvironments is poorly understood. Here, we cocultured umbilical cord blood-derived MSCs with normal human epidermal keratinocytes to evaluate their paracrine effect in the presence of high extracellular calcium (Ca ) concentration. High Ca 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 Ca environment in transforming growth factors β1 (TGFβ1)-dependent manner. Furthermore, we determined that MSCs can regulate the mitogen-activated protein kinases, phosphatidylinositol 3-kinase/protein kinase B, and protein kinase C pathways in Ca -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 Ca environment as analyzed by a decrease in DNA synthesis, accumulation of phosphorylated retinoblastoma protein, 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. Stem Cells 2017;35:1592-1602.
间充质干细胞（MSCs）在改变的微环境中对角质形成细胞的影响尚不清楚。在此，我们将脐带血来源的MSCs与人正常表皮角质形成细胞共培养，以评估其在高细胞外钙（Ca）浓度存在下的旁分泌作用。高钙环境会导致角质形成细胞异常/过早分化，从而破坏正常的皮肤屏障功能。令人惊讶的是，我们发现MSCs在高钙环境下以转化生长因子β1（TGFβ1）依赖的方式抑制角质形成细胞的增殖和分化。此外，我们确定MSCs可以调节钙诱导分化的角质形成细胞中的丝裂原活化蛋白激酶、磷脂酰肌醇3激酶/蛋白激酶B和蛋白激酶C途径。与对照MSCs相比，敲低MSCs中的TGFβ1会导致分化抑制降低，角质形成细胞增殖显著增加。通过DNA合成减少、视网膜母细胞瘤蛋白磷酸化、cdc2积累以及p21 mRNA水平升高分析，MSCs来源的TGFβ1在高细胞外钙环境中进一步诱导角质形成细胞生长抑制，且独立于TGFβ1/SMAD途径。综上所述，我们发现MSCs来源的TGFβ1是角质形成细胞功能的关键调节因子，并涉及多个近端信号级联反应。《干细胞》2017年；35：1592 - 1602。
