Department of Applied Biology, Council of Scientific and Industrial Research(CSIR), Indian Institute of Chemical Technology, Hyderabad, TS, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
Department of Applied Biology, Council of Scientific and Industrial Research(CSIR), Indian Institute of Chemical Technology, Hyderabad, TS, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
Cytotherapy. 2019 Feb;21(2):260-273. doi: 10.1016/j.jcyt.2019.01.004. Epub 2019 Feb 7.
Neo-vascularization, an indispensible phenomenon for tissue regeneration, facilitates repair and remodeling of wound tissues. This process is impaired in chronic wounds due to reduced number and recruitment of endothelial cells (ECs), thereby necessitating development of newer strategies to enhance the EC repertoire as a therapeutic approach.
We explored the 'plasticity' of Wharton's jelly derived-mesenchymal stromal cells (WJ-MSCs) using an anti-inflammatory drug-mediated enhanced trans-differentiation into ECs, based on our observation of temporal decrease in COX-2 expression during trans-differentiation of MSCs into ECs at day 7 and 14 along with mature ECs.
At a physiological level, an increased DiI-labeled acetylated-low density lipoprotein (DiI-Ac-LDL) uptake, proliferation, migration and chick chorio allantoic membrane (CAM)-vasculogenesis occurred while at a molecular level significant up-regulation in messenger RNA (mRNA) and protein expression of endothelial-specific markers, Vegfr2, Pecam, eNOS, VE-Cadh and Tie-2, along with an activated p-VEGFR2 and its downstream mediators were observed in celecoxib-preconditioned ECs as compared with WJ-MSCs. Green fluorescent protein (GFP)-expressing stable WJ-MSCs and trans-differentiated EC-D14 in the absence/presence of celecoxib were generated using antibiotic selection for intradermal transplantation at the wound site on a murine 'excisional splinting wound' model. Engraftment of transplanted human cells in immunosuppressant-treated mice was confirmed by a significant increase in the expression levels of human gene-specific endothelial markers at the regenerated wound sites. Morphometrically, increased vascularity and percent wound closure were observed in regenerated wounds of mice transplanted with celecoxib-preconditioned-EC-D14.
Cox-2 inhibition led to an enhanced trans-differentiation of WJ-MSCs into ECs that, when transplanted, accelerated the skin regeneration by engraftment and neo-vascularization at the wound bed, suggesting a plausible new therapeutic role of celecoxib.
新生血管化是组织再生不可或缺的现象，它促进了伤口组织的修复和重塑。然而，在慢性伤口中，由于内皮细胞（ECs）数量减少和募集减少，这一过程受到损害，因此需要开发新的策略来增强 EC 谱作为一种治疗方法。
我们观察到间充质干细胞（MSCs）向 ECs 转化过程中 COX-2 表达在第 7 天和第 14 天逐渐降低，同时观察到成熟 ECs 也有这种情况，基于这一观察结果，我们使用一种抗炎药物介导的增强转化方法，探索了牙髓基质衍生间充质干细胞（WJ-MSCs）的“可塑性”，使它们向 EC 转化。
在生理水平上，我们观察到 DiI 标记的乙酰化低密度脂蛋白（DiI-Ac-LDL）摄取、增殖、迁移和鸡胚绒毛尿囊膜（CAM）血管生成增加，而在分子水平上，内皮特异性标志物的信使 RNA（mRNA）和蛋白表达显著上调，Vegfr2、Pecam、eNOS、VE-Cadh 和 Tie-2 等，同时在 Celecoxib 预处理 ECs 中观察到 p-VEGFR2 及其下游介质的激活。与 WJ-MSCs 相比，无/有 Celecoxib 预处理的 GFP 稳定表达 WJ-MSCs 和转化的 EC-D14 用于在鼠“切除夹板伤口”模型的伤口部位进行皮内移植。在接受免疫抑制剂治疗的小鼠中，通过在再生伤口部位人基因特异性内皮标志物的表达水平显著增加，证实了移植的人细胞的植入。形态学上，在接受 Celecoxib 预处理-EC-D14 移植的小鼠再生伤口中观察到血管生成增加和伤口闭合百分比增加。
COX-2 抑制导致 WJ-MSCs 向 ECs 的转化增强，当移植时，通过在伤口床的植入和新生血管化加速皮肤再生，这表明 Celecoxib 可能具有新的治疗作用。
