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As the nervous system exerts direct and indirect effects on stem cells mobilization and catecholamines mobilize hematopoietic stem cells, we hypothesized that dopamine might induce mesenchymal progenitor cells (MPCs) mobilization. We show that dopamine induced in vitro MPCs migration through D2-class receptors, and their alternative phosphoinositide 3-kinase/Akt pathways. Also, administration of catecholamines induced in vivo mobilization of colony-forming unit-fibroblast in mice. In contrast, in vitro and in vivo MPCs migration was suppressed by D2-class receptors antagonists and blocking antibodies, consistent with dopamine signaling pathway implication. In humans, patients treated with L-dopa or catecholaminergic agonists showed a significant increase of a MPC-like population (CD45-CD31-CD34-CD105+) in their peripheral blood. These findings reveal a new link between catecholamines and MPCs mobilization and suggest the potential use of D2-class receptors agonists for mobilization of MPCs in clinical settings. We thank Iván Gutierrez, Ander Abarrategi, Manuel Masip, Mar Arriero, and Daniel Pérez for his assistance in several techniques. This work was supported by grants from the Fondo de Investigaciones Sanitarias (FIS; PI05/2217 and PI08/0029), the Madrid Regional Government (S‐BIO‐0204–2006, MesenCAM; P2010/BMD‐2420, CellCAM) in Spain, and Consejería de Salud de la Junta de Andalucía (0027/2006) to J.G.‐C. The experiments were approved by the appropriate committees. Sí

The cellular microenvironment plays a relevant role in cancer development. We have reported that mesenchymal stromal/stem cells (MSCs) deficient for p53 alone or together with RB (p53(-/-)RB(-/-)) originate leiomyosarcoma after subcutaneous (s.c.) inoculation. Here, we show that intrabone or periosteal inoculation of p53(-/-) or p53(-/-)RB(-/-) bone marrow- or adipose tissue-derived MSCs originated metastatic osteoblastic osteosarcoma (OS). To assess the contribution of bone environment factors to OS development, we analyzed the effect of the osteoinductive factor bone morphogenetic protein-2 (BMP-2) and calcified substrates on p53(-/-)RB(-/-) MSCs. We show that BMP-2 upregulates the expression of osteogenic markers in a WNT signaling-dependent manner. In addition, the s.c. coinfusion of p53(-/-)RB(-/-) MSCs together with BMP-2 resulted in appearance of tumoral osteoid areas. Likewise, when p53(-/-)RB(-/-) MSCs were inoculated embedded in a calcified ceramic scaffold composed of hydroxyapatite and tricalciumphosphate (HA/TCP), tumoral bone formation was observed in the surroundings of the HA/TCP scaffold. Moreover, the addition of BMP-2 to the ceramic/MSC implants further increased the tumoral osteoid matrix. Together, these data indicate that bone microenvironment signals are essential to drive OS development.

Human sarcomas have been modeled in mice by expression of specific fusion genes in mesenchymal stem cells (MSCs). However, sarcoma models based on human MSCs are still missing. We attempted to develop a model of liposarcoma by expressing FUS (FUsed in Sarcoma; also termed TLS, Translocated in LipoSarcoma)-CHOP (C/EBP HOmologous Protein; also termed DDIT3, DNA Damage-Inducible Transcript 3), a hallmark mixoid liposarcoma-associated fusion oncogene, in wild-type and p53-deficient mouse and human adipose-derived mesenchymal stem/stromal cells (ASCs). FUS-CHOP induced liposarcoma-like tumors when expressed in p53−/− but not in wild-type (wt) mouse ASCs (mASCs). In the absence of FUS-CHOP, p53−/− mASCs forms leiomyosarcoma, indicating that the expression of FUS-CHOP redirects the tumor genesis/phenotype. FUS-CHOP expression in wt mASCs does not initiate sarcomagenesis, indicating that p53 deficiency is required to induce FUS-CHOP-mediated liposarcoma in fat-derived mASCs. In a human setting, p53-deficient human ASCs (hASCs) displayed a higher in vitro growth rate and a more extended lifespan than wt hASCs. However, FUS-CHOP expression did not induce further changes in culture homeostasis nor initiated liposarcoma in either wt or p53-depleted hASCs. These results indicate that FUS-CHOP expression in a p53-deficient background is sufficient to initiate liposarcoma in mouse but not in hASCs, suggesting the need of additional cooperating mutations in hASCs. A microarray gene expression profiling has shed light into the potential deregulated pathways in liposarcoma formation from p53-deficient mASCs expressing FUS-CHOP, which might also function as potential cooperating mutations in the transformation process from hASCs.

Previous studies have shown the relevance of bone marrow-derived MSCs (BM-MSCs) in controlling graft-versus-host disease (GVHD) after allogeneic transplantation. Since adipose tissue-derived MSCs (Ad-MSCs) may constitute a good alternative to BM-MSCs, we have expanded MSCs derived from human adipose tissue (hAd-MSCs) and mouse adipose tissue (mAd-MSCs), investigated the immunoregulatory properties of these cells, and evaluated their capacity to control GVHD in mice. The phenotype and immunoregulatory properties of expanded hAd-MSCs were similar to those of human BM-MSCs. Moreover, hAd-MSCs inhibited the proliferation and cytokine secretion of human primary T cells in response to mitogens and allogeneic T cells. Similarly, ex vivo expanded mAd-MSCs had an equivalent immunophenotype and exerted immunoregulatory properties similar to those of hAd-MSCs. Moreover, the infusion of mAd-MSCs in mice transplanted with haploidentical hematopoietic grafts controlled the lethal GVHD that occurred in control recipient mice. These findings constitute the first experimental proof that Ad-MSCs can efficiently control the GVHD associated with allogeneic hematopoietic transplantation, opening new perspectives for the clinical use of Ad-MSCs.