Results in our recent publication in Journal ofInvestigative Dermatology (pii: S0022-202X(16)32239-4)demonstrate that skin commensal bacteria can exploitglycerol fermentation to produce various short-chainfatty acids (SCFAs). SCFAs can act on host cells throughinhibition of histone deacetylase (HDAC). Butyricacid, one of SCFAs, has been shown to enhance preadipocytedifferentiation to adipocytes via its HDACinhibitory activity. The precise mechanism in which SCFAsinduce adipogenic differentiation is currentlyunclear. Activation of PPAR-γ increased the expression ofperilipin A, a protein on the periphery of lipiddroplets, indicating that PPAR-γ plays a role in lipiddroplet formation. Our data demonstrate that adiposederivedstem cells (ADSCs) treated with SCFAs enhanced theintracellular accumulation of Oil Red Ostained lipids and that knockdown of PPAR-γ decreased theexpression of SCFA analog-induced perilipin A.These results suggest that SCFA increases the accumulationof lipid droplets and induces adipogenicdifferentiation of ADSCs via PPAR-γWe hypothesize that the skin commensal bacteria and/ortheir fermentation products includingSCFAs distributed in the deep skin can stimulate theadipogenic differentiation of adipose stem cells (ASCs)through HDAC inhibition and PPAR-γ activation. ThreeSpecific Aims are proposed to verify ourhypothesis. In Specific Aim 1, we will quantify the localconcentrations of SCFAs by capillaryultrafiltration (CUF) probes in conjunction with NMR/HPLCanalysis, and induce the adipogenicdifferentiation of ASC in vivo by mono-association withskin commensals in mice. In Specific Aim 2, wewill investigate the effect of SCFA deficiency on theadipogenic differentiation of ASC using germfree/SCFAdeficient mice, and measure the SCFA deficiency anddecreased HDAC activity in germ-freemice. In Specific Aim 3, we will verify the requirement ofHDAC inhibition for induction of adipogenicdifferentiation, and confirm the essential role of PPAR-γin the signaling pathway of bacterial fermentationSCFAHDAC/PPAR-γ-adipogenesis.An injectable adipocyte filler for soft tissue augment hasbeen developed from cultured ASCs.However, multiple questions remain regarding the viabilityof ASCs, the requirement of biologicalscaffolds, and the repeated injection schedule in theformation of future fat graft replacements. Ourproposal will validate the potential for SCFAs to enhancethe adipogenic differentiation and the viability ofASCs, reducing the need for repeated injections, andthereby achieving a more permanent solution for softtissue augmentation.
|Effective start/end date
|1/10/20 → 30/09/21
In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):