Tissue-specific angiogenic and invasive properties of human neonatal thymus and bone MSCs: Role of SLIT3-ROBO1

Abstract

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.

Stromal Cell-SLIT3/Cardiomyocyte-ROBO1 Axis Regulates Pressure Overload-Induced Cardiac Hypertrophy

“… 24 Furthermore, we previously determined that human mesenchymal stem/stromal cells, which also reside in the perivascular region, 43 expressed SLIT3. 44 As such, we considered the possibility that SLIT3 derived from vascular mural cells in the heart may also play a role in regulating cardiac hypertrophy. To specifically target vascular mural cells, we utilized a Tbx18-CreERT2 mouse that has been previously generated and characterized extensively to be a vascular mural cell–specific Cre mouse line with minimal crossover into fibroblasts, endothelial cells, and cardiomyocytes.…”

Age-linked lung pathology is reduced by immunotherapeutic targeting of isoDGR protein damage

“…Aging is the primary risk factor for many chronic diseases that increase risk of early mortality. As the global population becomes more elderly, current projections suggest this will drive an exponential increase in worldwide burden of age-linked diseases and associated healthcare costs 46,47 . Consequently, there is an urgent need to better understand the complex processes that underpin human aging, so that we can begin to develop methods of extending health lifespan in elderly cohorts.…”

Acquisition of Immune Privilege in GBM Tumors: Role of Prostaglandins and Bile Salts

“…In the cross-correlation studies, the data from the human brain vascular atlas were used to identify markers of perivascular fibroblasts (FBLN1, FBN1, GPC3, and ROR2) [ 123 ], and angiogenic mesenchymal stem cell/smooth muscle was identified by utilizing SLIT3 [ 124 , 125 ].…”