However, further studies are needed to optimize their therapeutic use in preclinical models of MM as well as to define their efficacy and safety profiles for future cell-based gene therapies for the clinical setting. Supplementary Material Supplemental data:Click here to view.(182K, pdf) Acknowledgments This work was supported by a grant from the Italian Association for Cancer Research (AIRC, IG11647) and from the Italian Ministry for the University and Research (PRIN 2010). peritumoral injections of the same MSC subtype significantly delayed the tumor burden growing in subcutaneous plasmocytoma-bearing mice. Finally, both microarrays and ELISA revealed different expression of several genes and soluble factors in UC-MSCs as compared with other MSCs. Our data suggest that UC-MSCs have a distinct molecular profile that correlates with their intrinsic anti-MM activity and emphasize the UCs as ideal sources of MSCs for future cell-based therapies against MM. Introduction Mesenchymal stromal cells (MSCs) constitute the stroma of organs and tissues, and they contain a subset of stem cells with self-renewal and differentiation potential . Besides the bone marrow (BM), MSCs are abundant in excess fat as adipose (AD) MSCs and in perivascular connective tissues such as the umbilical cord (UC) Wharton’s jelly, as well as in other fetal or adult tissues where they act as dynamic cells for tissue repair and regeneration [2C4]. Extensive studies in xenogenic tumors have described that MSCs are chemoattracted toward the tumor microenvironment where they exert controversial effects as supporters or inhibitors of the tumor progression , whereas major data exploring the role of BM-MSCs in multiple myeloma (MM) definitely support their stimulatory activity on MM cell growth [6,7]. The growth of MM cell clones within the BM is basically sustained by BM-MSCs that, once stimulated by malignant plasma cells, upgrade their secretion of interleukin (IL)-6, a major growth factor for MM cells [8C10]. Moreover, direct molecular interactions of MSCs with other molecules such as CD44, very late antigen ?4 and ?5, vascular cell adhesion-1, and syndecan-1 on MM cells , in association to inflammatory cytokines, pro-angiogenic and pro-osteoclastogenic molecules secreted in response to the cell-to-cell cross-talk, contribute to tumor expansion . Nevertheless, a suppressive activity of MSCs on MM cell growth has also been reported, both in vitro and in animal models of the human disease . We have recently exhibited that AD-MSCs stably designed to express the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) efficiently migrate toward MM cells and exert anti-MM cytotoxicity in vitro , while others showed that MM-bearing SCID-rab mice injected PROTAC Mcl1 degrader-1 with placenta-derived MSCs underwent dramatic inhibition of tumor growth within the bone . Despite these encouraging data PROTAC Mcl1 degrader-1 and PROTAC Mcl1 degrader-1 successful MSC-based approaches in different solid tumors [16C18], the therapeutic potential of MSCs in MM is usually debated and largely dismissed in view of their supportive role in MM cell growth. Molecular studies of BM-MSCs from MM patients EIF4EBP1 compared with healthy controls have, indeed, revealed recurrent genomic imbalances as deregulation of several genes , chromosomal gains and losses , and upregulation of factors implicated in MM progression and bone disease . It has also been exhibited that even normal MSCs co-cultured with MM cells undergo the genomic and phenotype alterations common of MSCs derived from BM of MM patients . Thus, the environment permissive for MM growth is usually attributable to genomic and secretory aberrations induced in quiescent MSCs by malignant plasma cells, which generate an inflamed marrow milieu where different soluble factors support the clonal growth of MM cells . Although the genomic conditioning of BM-MSCs in MM patients is usually apparently correlated to the extent of marrow and skeletal involvement, recent studies suggest that fetal MSCs, as those from placenta, are resistant to genomic aberrations induced by MM cells and exert a tumor-restraining effect in a mouse model of MM . The suppression of Burkitt’s lymphoma cell proliferation by UC-MSCs, indeed, emphasizes the native tumoricidal property of fetal MSCs in hematological malignancies . Here, we investigated the effects of UC-MSCs as compared with AD-MSCs, as well as with normal and myelomatous BM-MSCs in co-cultures with MM cells. We found that healthy UC-MSCs definitely suppress myeloma cell growth both in vitro and in MM-bearing mice. Genomic and proteomic analyses of fetal MSCs revealed a variable content of anti-inflammatory and anti-proliferative factors that.