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Jun 17, 2011

Specific Adipose Stromal Cell Surface Receptor and Ligand Identified

Specific Adipose Stromal Cell Surface Receptor and Ligand Identified

Researchers suggest findings could point to new therapeutic directions for obesity and metabolic diseases.[© serdarduran - Fotolia.com]

  • Scientists say they have identified a cell surface marker specific to the adipose stromal cells (ASCs) that are the progenitors for white adipose tissue (WAT). The team claims the cell surface receptor, delta decorin (ΔDCN), is differentially expressed on ASCs, and has as its ligand resistin, an adipokine for which a receptor had not previously been identified.

    The researchers from University of Texas Health Science Center’s Brown Foundation found that expression of ΔDCN in a well-characterized mouse preadipocyte cell line promoted proliferation and migration but suppressed lipid accumulation upon adipogenesis induction, which was resistin dependent.

    Mikhail G. Kolonin, Ph.D., and colleagues describe their findings in Cell Stem Cell in a paper titled “An Isoform of Decorin Is a Resistin Receptor on the Surface of Adipose Progenitor Cells.”

    Identifying ASCs in a pool of different types of mesenchymal stem cells has previously been based on an unreliable approach utilizing a combination of semispecific markers, explains Dr. Kolonin, who is assistant professor of molecular medicine at the UTHealth Medical School.  

    To try and identify ASC-specific markers the researchers used a phage display technique to screen combinatorial libraries for peptides binding to differentially expressed, circulation-accessible stromal cell molecules in live mice. They isolated a cyclic peptide called WAT7, which specifically homed in on ASCs but not stromal cells in other organs, when administered systemically.

    They then used WAT7 as bait to biochemically isolate the corresponding ASC surface receptor, which was identified as  a proteolytic cleavage fragment of decorin (DCN) that lacked a glycanation site and which they designated ΔDCN.

    Several approaches were used to confirm that ΔDCN is expressed on the surface of ASCs. Interestingly, WAT7 localized to the surface of ASCs that face away from a blood vessel. This suggests that ΔDCN itself, which also localized on these ASC surface domains, may be involved in interaction with interstitial ECM and adipocytes, the researchers remark.

    Finally, in a screen for proteins mimicked by WAT7, the team identified resistin (also known as adipocyte-specific secretory factor, or ADSF) as a protein that serves as an endogenous ligand of ΔDCN in WAT. This came as something of a surprise, as there is no other published literature directly linking DCN with the adipokine, they point out.

    “The decorin-resistin connection is particularly interesting because both decorin and resistin have previously been implicated in type 2 diabetes and other inflammatory-related diseases,” Dr. Kolonin notes.

    Having identified ΔDCN and its ligand, resistin, the researchers went on to carry out functional analysis of ΔDCN-resistin interaction in a mouse preadipocyte cell line that is widely used for studying the biology of adipocyte progenitors. Cells expressing fluorescently tagged ΔDCN proliferated, whereas cells expressing full length DCN did not undergo proliferation.

    Likewise, there was an increase in the motility of ΔDCN-expressing cells, whereas full-length DCN-expressing cells showed the opposite trend. When the cells were subjected to adipogenesis induction, the formation of large lipid droplets in fully length DCN-expressing cells was mildly inhibited, whereas ΔDCN expression notably inhibited the formation of large lipid droplets.

    They then showed that administering exogenous resistin further promoted cell proliferation and migration in ΔDCN-expressing cells. The reverse was observed for adipocyte differentiation: depletion of resistin partially restored normal lipid accumulation, whereas extra resistin exacerbated the lipogenesis defect.

    “Combined, these data indicate that ΔDCN activates a cellular program favoring proliferation and migration of adipocyte progenitors, while at the same time affecting the lipogenesis/lipolysis program,” the authors write.

    DCN is a secreted multifunctional proteoglycan that plays a role in cell adhesion, proliferation, and migration, they add. The protein has also been implicated in a number of pathological conditions. Resistin has been established as a hormone secreted predominantly by adipocytes in WAT and as a key regulatory of metabolism.  The molecule promotes cell proliferation and migration while inhibiting adipogenesis.

    “It appears striking that its reported effects on preadipocyte physiology match those induced by ΔDCN expression, which are distinct from the reported inhibitory effects of full-length DCN on cell proliferation and migration as well as on adipogenesis,” the authors point out.

    They admit that at this point it isn’t clear whether ΔDCN inhibits adipocyte differentiation or if it maintains the committed adipocyte in a less advanced state of differentiation with better-accessible, smaller lipid droplets in a state of activated lipolysis. However, building on an existing hypothesis of resistin secreted by adipocytes functioning as a feedback regulator of adipocyte differentiation, the team proposes that its action on adipose progenitors is executed via ΔDCN-mediated signalling.

    “Our study demonstrates that it is possible to direct probes to perivascular stromal cells in vivo in an organ specific manner,” the team concludes. “In the future, the cell surface interaction between ΔDCN and resistin can be exploited for imaging or therapeutic ASC targeting.”

    Dr. Kolonin adds, “the next step will involve preclinical testing to see if we can develop the identified peptide into compounds that target these adipose stem cells. By depleting the adipose tissue progenitors, we may be able to provide long-term control of white fat.”


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