Ledford Benjamin T, Chen Miao, Van Dyke Mark, Barron Catherine, Zhang Xiaonan, Cartaya Aurora, Zheng Youjing, Ceylan Ahmet, Goldstein Aaron, He Jia-Qiang
Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, 24061, USA.
Department of Biomedical Engineering, College of Engineering, University of Arizona, Tucson, AZ, 85721, USA.
Stem Cell Rev Rep. 2023 Oct;19(7):2341-2360. doi: 10.1007/s12015-023-10574-6. Epub 2023 Jul 1.
Peripheral artery disease (PAD) is a common vascular disorder in the extremity of limbs with limited clinical treatments. Stem cells hold great promise for the treatment of PAD, but their therapeutic efficiency is limited due to multiple factors, such as poor engraftment and non-optimal selection of cell type. To date, stem cells from a variety of tissue sources have been tested, but little information is available regarding vascular smooth muscle cells (VSMCs) for PAD therapy. The present study examines the effects of keratose (KOS) hydrogels on c-kit/CD31 cardiac vascular smooth muscle progenitor cell (cVSMPC) differentiation and the therapeutic potential of the resultant VSMCs in a mouse hindlimb ischemic model of PAD. The results demonstrated that KOS but not collagen hydrogel was able to drive the majority of cVSMPCs into functional VSMCs in a defined Knockout serum replacement (SR) medium in the absence of differentiation inducers. This effect could be inhibited by TGF-β antagonists. Further, KOS hydrogel increased expression of TGF-β-associated proteins and modulated the level of free TGF-β during differentiation. Finally, transplantation of KOS-driven VSMCs significantly increased blood flow and vascular densities of ischemic hindlimbs. These findings indicate that TGF-β signaling is involved in KOS hydrogel-preferred VSMC differentiation and that enhanced blood flow are likely resulted from angiogenesis and/or arteriogenesis induced by transplanted VSMCs.
外周动脉疾病（PAD）是肢体末端常见的血管疾病，临床治疗手段有限。干细胞在PAD治疗方面具有巨大潜力，但其治疗效率因多种因素而受限，如低植入率和细胞类型选择不佳等。迄今为止，已对多种组织来源的干细胞进行了测试，但关于用于PAD治疗的血管平滑肌细胞（VSMC）的信息却很少。本研究考察了角质素（KOS）水凝胶对c-kit/CD31心脏血管平滑肌祖细胞（cVSMPC）分化的影响，以及在PAD小鼠后肢缺血模型中所得VSMC的治疗潜力。结果表明，在不含分化诱导剂的限定性敲除血清替代物（SR）培养基中，KOS水凝胶而非胶原蛋白水凝胶能够促使大多数cVSMPC分化为功能性VSMC。这种效应可被TGF-β拮抗剂抑制。此外，KOS水凝胶在分化过程中增加了TGF-β相关蛋白的表达并调节了游离TGF-β的水平。最后，移植由KOS诱导分化的VSMC显著增加了缺血后肢的血流量和血管密度。这些发现表明，TGF-β信号通路参与了KOS水凝胶偏好的VSMC分化，且血流量的增加可能是由移植的VSMC诱导的血管生成和/或动脉生成所致。
