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ASSESSMENT OF SIGNALING PATHWAYS TO ACTIVATE ADIPOSE-DERIVED STEM/STROMAL CELLS (ASCS) AFTER ADIPOSE TISSUE INJURY: POSSIBLE THERAPEUTIC TOOLS FOR ADIPOGENSIS AND ANGIOGENESIS
Presenter: Shinichiro Kuno, Graduate Student
Co-Authors: Doi K; Mineda K; Kinoshita K; Kato H; Yoshimura K
University of Tokyo

Introduction: Chemokines and damage-associated molecular pattern molecules (DAMPs) are involved in activation and/or attraction of resident or mobilized stem/progenitor cells in immune-response after tissue injury. We sought to dissect mechanisms activating stem cells after adipose tissue (AT) damage for establishing a therapeutic strategy using damage-associated factors.

Methods: Microarray assay was performed for freshly isolated ASCs, AT-resident macrophages (ATM) and circulating monocytes. Chemokine receptor expression such as CXCRs on ASCs was also examined. AT-damage-associated factors were collected as AT soaked buffer (ATSB) by incubating a fragmented AT in buffered saline for various periods. ASC reactions were examined after stimulation of ATSB, other damage associated factors, or ligands to CXCRs. ATSB components were analyzed by cytokine array and ELISA.

Results: ATSB, significantly promoted ASC proliferation, migration and capillary-like network formation. Microarray revealed that, among chemokine receptors, CXCR7 (receptor for SDF-1 and I-TAC) gene expression was upregulated in ASCs. Expression of CXCR7 on fresh ASCs was also confirmed by flowcytometory and immunocytochemistory, while ASCs rarely expressed CXCR4. ASCs showed more enhanced migration in response to SDF-1 than I-TAC and ATSB, while I-TAC and ATSB promoted ASC proliferation more than SDF-1. Slightly higher level of network formation was observed in ATSB-treated group compared to SDF-1 or I-TAC group. Cytokine array(figure1) and ELISA revealed that ATSB contained damage-associated factors such as HMGB1 and inflammatory cytokines including I-TAC. ATSB incubated for longer periods contained more damage-associated factors and showed higher ASC-activating effects.

Discussions: It was suggested that ASCs were differentially activated and attracted in the wound healing process after AT damage. In the initial phase, damage-associated factors and inflammatory cytokines were released from the damaged AT and activated ASCs. SDF-1, which appears in the secondary phase of wound healing, substantially promoted migration of ASCs.


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