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Junctional adhesion molecules (JAMs) are expressed in diverse types of stem and progenitor cells, but their physiological significance has yet to be established. Here, we report that JAMs exhibit a novel mode of interaction and biological activity in adipose-derived stromal/stem cells (ADSCs). Among the JAM family members, JAM-B and JAM-C were concentrated along the cell membranes of mouse ADSCs. JAM-C but not JAM-B was broadly distributed in the interstitial spaces of mouse adipose tissue. Interestingly, the JAM-C ectodomain was cleaved and secreted as a soluble form (sJAM-C) in vitro and in vivo, leading to deposition in the fat interstitial tissue. When ADSCs were grown in culture plates coated with sJAM-C, cell adhesion, cell proliferation and the expression of five mesenchymal stem cell markers, <i>Cd44</i>, <i>Cd105</i>, <i>Cd140a</i>, <i>Cd166</i> and <i>Sca-1</i>, were significantly elevated. Moreover, immunoprecipitation assay showed that sJAM-C formed a complex with JAM-B. Using CRISPR/Cas9-based genome editing, we also demonstrated that sJAM-C was coupled with JAM-B to stimulate ADSC adhesion and maintenance. Together, these findings provide insight into the unique function of sJAM-C in ADSCs. We propose that JAMs contribute not only to cell–cell adhesion, but also to cell–matrix adhesion, by excising their ectodomain and functioning as a niche-like microenvironment for stem and progenitor cells.