Systemically Delivered Adipose Stromal Vascular Fraction Cells Disseminate to Peripheral Artery Walls and Reduce Vasomotor Tone Through a CD11b+ Cell-Dependent Mechanism

Abstract

Vasoactivity, an important aspect of tissue healing, is often compromised in disease and tissue injury. Dysfunction in the smaller vasoactive arteries is most impactful, given the role of these vessels in controlling downstream tissue perfusion. The adipose stromal vascular fraction (SVF) is a mix of homeostatic cells shown to promote tissue healing. Our objective was to test the hypothesis that autologous SVF cells therapeutically modulate peripheral artery vasoactivity in syngeneic mouse models of small artery function. Analysis of vasoactivity of saphenous arteries isolated from normal mice 1 week after intravenous injection of freshly isolated SVF cells revealed that pressure-dependent artery vasomotor tone was decreased by the SVF cell isolate, but not one depleted of CD11b(+) cells. Scavenging hydrogen peroxide in the vessel wall abrogated the artery relaxation promoted by the SVF cell isolate. Consistent with a CD11b(+) cell being the relevant cell type, SVF-derived F4/80-positive macrophages were present within the adventitia of the artery wall coincident with vasorelaxation. In a model of artery inflammation mimicking a common disease condition inducing vasoactive dysfunction, the SVF cells potentiated relaxation of saphenous arteries without structurally remodeling the artery via a CD11b(+) cell-dependent manner. Our findings demonstrate that freshly isolated, adipose SVF cells promote vasomotor relaxation in vasoactive arteries via a hydrogen peroxide-dependent mechanism that required CD11b(+) cells (most likely macrophages). Given the significant impact of small artery dysfunction in disease, we predict that the intravenous delivery of this therapeutic cell preparation would significantly improve tissue perfusion, particularly in diseases with diffuse vascular involvement.

Macrophages: An Inflammatory Link Between Angiogenesis and Lymphangiogenesis

“…Hence, it is important to consider which cell type dominates in a dynamic growth and remodeling setting and how different cell types influence one another (e.g., mesenchymal stem cells and macrophages). This point was recently highlighted by a study showing that the therapeutic effects of adipose-derived progenitor cells was dependent on the presence of CD11b+ macrophages [185].…”

Adipose‐resident myeloid‐derived suppressor cells modulate immune cell homeostasis in healthy mice

“…CD11b + CD301 À Ly6C Hi Ly6G À and Ly6C Low Ly6G + cells are in AT from metabolically healthy mice Previous work in our laboratory has examined the therapeutic value of the AT SVF in improving vascular function. [16][17][18] In one study the SVF isolate lost many of its beneficial effects when the CD11b + cells were depleted. 17 Further characterization of these therapeutically relevant CD11b + cells found that approximately 45% of were also Gr1 + .…”

“…[16][17][18] In one study the SVF isolate lost many of its beneficial effects when the CD11b + cells were depleted. 17 Further characterization of these therapeutically relevant CD11b + cells found that approximately 45% of were also Gr1 + . Similar populations of CD11b + Gr1 + cells have been observed by others in the AT of healthy, control animals, 4,5 yet no detailed characterization of these cells has been performed.…”

Development of a vascularized, induced pluripotent stem cell-derived liver-tissue mimic for therapeutic applications.

“…The cellular composition of each hSVF batch is likely to be different depending on factors such as gender, age, and social lifestyle (e.g. smoking, alcohol use), all of which likely have significant effects on cell viability and cellular function., Prior studies have indicated that the proportion of CD31 + EC is decreased with culture SVF cells as opposed to freshly isolated cells 9,400 . In spite of these factors, we observed the same trends with each hSVF isolation, regardless of the patient demographics.…”

“…After implantation for two weeks, host animals were sacrificed and the constructs explanted, processed and analyzed as described in the Materials and Methods ( Figure 20A). Each experimental condition was quantified for length density (i.e., a ratio of the total EC length to the 3D scan volume; Figure 20B) as well as the Adipose SVF is a heterogeneous cell population that contains EC, perivascular cells, macrophage, fibroblasts and stem cells 9,369,400 . This endogenous heterogeneity is likely what imbues the cellular system with the specific capacity to form functional microvasculatures in vivo 1,9,370 .…”