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SDF-1 Regulates Adipose Niche Homeostasis and Adipose Derived Stromal Cell Function
Zeshaan N. Maan, MBBS, MS, MRCS, Robert C. Rennert, BA, Dominik Duscher, MD, Michael Januszyk, MD, Kevin Paik, BA, Michael T. Chung, BA, Kevin Paik, BA, Toshihiro Fujiwara, MD, PhD, Melanie Rodrigues, PhD, Natalie Ho, High school, Hutton Baker, High school, Marcelina Perez, BA, Michael Hu, MD, MPH, Michael Sorkin, MD, Michael T. Longaker, MD, MBA, Geoffrey C. Gurtner, MD, FACS.
Stanford University School of Medicine, Stanford, CA, USA.
Chronic, poorly healing wounds, typically occurring in the setting of diabetes, remain a significant problem in clinical practice. Adipose derived stromal cells (ASCs) are gaining increased attention for wound healing applications. Unfortunately, diabetes affects the ASC niche environment and impairs the neovascular potential of ASCs, thereby reducing their efficacy in augmenting wound healing, limiting the therapeutic potential of autologous cell-based approaches. The factors involved in maintaining the ASC niche microenvironment are incompletely understood, though recent studies have suggested a role for endothelial cell-stromal interactions, potentially mediated by stromal-cell derived factor 1 (SDF-1). Interestingly, SDF-1 expression has been shown to be impaired in the setting of diabetes. Using a novel, Cre-lox genetic knockout, murine model, we studied the effect of global (gKO) and endothelial cell-specific SDF-1 knockout (eKO) on the ASC niche environment and ASC function.
Inguinal fat pads were harvested from wild type (WT), diabetic, gKO and eKO mice. Whole tissue, representing the ASC niche, was processed for qRT-PCR. Primary cells were harvested from the fat for FACS analysis and cell culture. BrdU proliferation assay, human umbilical vein endothelial cell (HUVEC) co-culture tubulization assay in growth factor reduced (GFR) matrigel, adipogenic differentiation assay and survival assay were carried out on cells in passage 1.
ASCs from eKO and gKO mice demonstrated decreased proliferative capacity (*p<0.001) and survival (*p< 0.05) compared to WT, as well as decreased ability to induce tubulization of HUVECs (*p<0.01), similarly to diabetic ASCs. Adipogenic differentiation was significantly increased in eKO and gKO groups compared to WT (*p<0.01). eKO and gKO adipose tissue, representing the niche environment, demonstrated dramatic downregulation of FGF-2, VEGF, PDGF and their complimentary receptors, similarly to diabetic tissue (*p<0.001).
Endothelial cell-stromal interactions, mediated by SDF-1, play a pivotal role in maintaining ASC niche transcriptional homeostasis and preserving the functional capacity of ASCs. In the absence of SDF-1, ASCs are shunted towards adipogenesis, with reduced proliferative and pro-angiogenic capacity, impacting their physiological role within the adipose niche environment and their therapeutic potential in treating ischemia. The dysfunction of ASCs in diabetes may be related to downregulation of SDF-1 and subsequent disruption of the physiological cytokine milieu. Further investigation of the role of SDF-1 in ASC homeostasis and function, particularly in the context of diabetes, is ongoing to inform the development of autologous cell based therapies for diabetic wound healing.
Figure 1: ASCs deprived of SDF-1 have impaired capacity to promote endothelial cell tubulization.
Figure 2: Loss of SDF-1 expression disrupts the cytokine milieu of the ASC niche microenvironment, similarly to diabetes.
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