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Tissue-specific angiogenic and invasive properties of human neonatal thymus and bone MSCs: Role of SLIT3-ROBO1.
STEM CELLS Translational Medicine ( IF 6 ) Pub Date : 2020-05-29 , DOI: 10.1002/sctm.19-0448
Shuyun Wang 1 , Shan Huang 1 , Sean Johnson 1 , Vadim Rosin 1 , Jeffrey Lee 1 , Eric Colomb 1 , Russell Witt 2 , Alexander Jaworski 3 , Stephen J Weiss 4 , Ming-Sing Si 1
Affiliation  

Although mesenchymal stem/stromal cells (MSCs) are being explored in numerous clinical trials as proangiogenic and proregenerative agents, the influence of tissue origin on the therapeutic qualities of these cells is poorly understood. Complicating the functional comparison of different types of MSCs are the confounding effects of donor age, genetic background, and health status of the donor. Leveraging a clinical setting where MSCs can be simultaneously isolated from discarded but healthy bone and thymus tissues from the same neonatal patients, thereby controlling for these confounding factors, we performed an in vitro and in vivo paired comparison of these cells. We found that both neonatal thymus (nt)MSCs and neonatal bone (nb)MSCs expressed different pericytic surface marker profiles. Further, ntMSCs were more potent in promoting angiogenesis in vitro and in vivo and they were also more motile and efficient at invading ECM in vitro. These functional differences were in part mediated by an increased ntMSC expression of SLIT3, a factor known to activate endothelial cells. Further, we discovered that SLIT3 stimulated MSC motility and fibrin gel invasion via ROBO1 in an autocrine fashion. Consistent with our findings in human MSCs, we found that SLIT3 and ROBO1 were expressed in the perivascular cells of the neonatal murine thymus gland and that global SLIT3 or ROBO1 deficiency resulted in decreased neonatal murine thymus gland vascular density. In conclusion, ntMSCs possess increased proangiogenic and invasive behaviors, which are in part mediated by the paracrine and autocrine effects of SLIT3.

中文翻译:

人类新生儿胸腺和骨骼MSC的组织特异性血管生成和侵袭特性:SLIT3-ROBO1的作用。

尽管间充质干/基质细胞(MSCs)在许多临床试验中被研究为促血管生成和促增殖剂,但组织起源对这些细胞的治疗质量的影响知之甚少。供体年龄,遗传背景和供体健康状况的混杂影响使不同类型MSC的功能比较复杂化。利用临床环境,可以同时从同一新生患者的废弃但健康的骨骼和胸腺组织中分离出MSC,从而控制这些混杂因素,我们对这些细胞进行了体外和体内配对比较。我们发现新生儿胸腺(nt)MSC和新生儿骨骼(nb)MSC均表达不同的周细胞表面标志物谱。进一步,ntMSCs在体外和体内促进血管生成的能力更强,并且在体外入侵ECM方面也更能动和有效。这些功能差异部分由SLIT3的ntMSC表达增加介导,SLIT3是已知激活内皮细胞的因子。此外,我们发现SLIT3以自分泌方式通过ROBO1刺激了MSC的运动性和纤维蛋白凝胶的侵袭。与我们在人类MSC中的发现一致,我们发现SLIT3和ROBO1在新生鼠胸腺的血管周细胞中表达,而整体SLIT3或ROBO1缺乏导致新生鼠胸腺的血管密度降低。总之,ntMSC具有增加的促血管生成和侵袭行为,部分由SLIT3的旁分泌和自分泌作用介导。
更新日期:2020-05-29
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