Endocrine Research Unit, Veterans Affairs Medical Center, San Francisco, California, USA; Department of Medicine, University of California, San Francisco, California, USA.
Dermatology Department, Veterans Affairs Medical Center, San Francisco, California, USA.
J Invest Dermatol. 2019 Apr;139(4):919-929. doi: 10.1016/j.jid.2018.09.033. Epub 2018 Nov 4.
Extracellular Ca (Ca) is a crucial regulator of epidermal homeostasis and its receptor, the Ca-sensing receptor (CaSR), conveys the Ca signals to promote keratinocyte adhesion, differentiation, and survival via activation of intracellular Ca (Ca) and E-cadherin-mediated signaling. Here, we took genetic loss-of-function approaches to delineate the functions of CaSR in wound re-epithelialization. Cutaneous injury triggered a robust CaSR expression and a surge of Ca in epidermis. CaSR and E-cadherin were co-expressed at the cell-cell membrane between migratory keratinocytes in the nascent epithelial tongues. Blocking the expression of CaSR or E-cadherin in cultured keratinocytes markedly inhibited the wound-induced Ca propagation and their ability to migrate collectively. Depleting CaSR also suppressed keratinocyte proliferation by downregulating the E-cadherin/epidermal growth factor receptor/mitogen-activated protein kinase signaling axis. Blunted epidermal Ca response to wounding and retarded wound healing were observed in the keratinocyte-specific CaSR knockout (Casr) mice, whose shortened neo-epithelia exhibited declined E-cadherin expression and diminished keratinocyte proliferation and differentiation. Conversely, stimulating endogenous CaSR with calcimimetic NPS-R568 accelerated wound re-epithelialization through enhancing the epidermal Ca signals and E-cadherin membrane expression. These findings demonstrated a critical role for the CaSR in epidermal regeneration and its therapeutic potential for improving skin wound repair.
细胞外钙（Ca）是表皮稳态的关键调节剂，其受体钙敏感受体（CaSR）通过激活细胞内钙（Ca）和 E-钙黏蛋白介导的信号转导，传递 Ca 信号以促进角质形成细胞黏附、分化和存活。在这里，我们采用遗传功能丧失方法来描绘 CaSR 在伤口再上皮化中的功能。皮肤损伤引发了强烈的 CaSR 表达和表皮中 Ca 的激增。CaSR 和 E-钙黏蛋白在新生上皮舌状突起中迁移的角质形成细胞之间的细胞-细胞膜上共同表达。在培养的角质形成细胞中阻断 CaSR 或 E-钙黏蛋白的表达，显著抑制了伤口诱导的 Ca 传播及其集体迁移的能力。CaSR 的耗竭还通过下调 E-钙黏蛋白/表皮生长因子受体/丝裂原活化蛋白激酶信号轴抑制角质形成细胞增殖。角质形成细胞特异性 CaSR 敲除（Casr）小鼠的表皮对创伤的 Ca 反应减弱，伤口愈合延迟，其新生上皮的 E-钙黏蛋白表达下降，角质形成细胞增殖和分化减少。相反，用钙敏感受体激动剂 NPS-R568 刺激内源性 CaSR 通过增强表皮 Ca 信号和 E-钙黏蛋白膜表达来加速伤口再上皮化。这些发现表明 CaSR 在表皮再生中具有关键作用及其改善皮肤伤口修复的治疗潜力。
