Patrick Laharrague

Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells.

Like mesenchymal stem cells from bone marrow (BM‐MSCs), adipose tissue‐derived adult stem cells (ADAS cells) can differentiate into several lineages and present therapeutical potential for repairing damaged tissues. The use of allogenic stem cells can enlarge their therapeutical interest, provided that the grafted cells could be tolerated. We investigate here, for the first time, the immunosuppressive properties of ADAS cells compared with the well‐characterized immunosuppressive properties of BM‐MSCs. ADAS cells did not provoke in vitro alloreactivity of incompatible lymphocytes and, moreover, suppressed mixed lymphocyte reaction (MLR) and lymphocyte proliferative response to mitogens. The impairment of inhibition when ADAS cells and BM‐MSCs were separated from lymphocytes by a permeable membrane suggests that cell contact is required for a full inhibitory effect. Hepatocyte growth factor is secreted by both stem cells but, similar to interleukin‐10 and transforming growth factor‐β (TGF‐β), the levels of which were undetectable in supernatants of MLR inhibited by ADAS cells or BM‐MSCs, it did not seem implicated in the stem cell suppressive effect. These findings support that ADAS cells share immunosuppressive properties with BM‐MSCs. Therefore, ADAS cell‐based reconstructive therapy could employ allogenic cells and because of their immunosuppressive properties, ADAS cells could be an alternative source to BM‐MSCs to treat allogenic conflicts.

A role for preadipocytes as macrophage-like cells

Several lines of evidence have supported a link betweeen adipose tissue and immunocompetent cells. This link is illustrated in obesity, where excess adiposity and impaired immune function have been described in both humans and genetically obese rodents. In addition, numerous factors involved in inflammatory response are secreted by both preadipocytes and macrophages. Here we show that proliferating preadipocytes in cell lines and primary cultures, develop phagocytic activity toward microorganisms. This is demonstrated by phagocytosis assays and confocal microscopy. This function disappears when preadipocytes stop proliferating and differentiate into adipocytes. After phagocytosis, preadipocytes show microbicide activity via an oxygen‐dependent mechanism. In addition, preadipocytes as well as adipocytes are stained with MOMA‐2, a marker of monocyte‐macrophage lineage, but are negative for specific mature macrophage markers (F4/80 and Mac‐1). These results suggest that preadipocytes could function as macro‐phage‐like cells and raise the possibility of a potential direct involvement of adipose tissue in inflammatory processes.—Cousin, B., Munoz, O., André, M., Fontanilles, A. M., Dani, C., Cousin, J. L., Laharrague, P., Casteilla, L., Pénicaud, L. A role for preadipocytes as macrophage‐like cells. FASEB J. 13, 305–312 (1999)

Transplantation of adipose derived stromal cells is associated with functional improvement in a rat model of chronic myocardial infarction

To determine the effect of transplantation of undifferentiated and cardiac pre‐differentiated adipose stem cells compared with bone marrow mononuclear cells (BM‐MNC) in a chronic model of myocardial infarction.

Human subcutaneous adipose cells support complete differentiation but not self-renewal of hematopoietic progenitors

Adipose tissue is now considered as an endocrine organ implicated in energy regulation, inflammation and immune response, and as a source of multipotent cells with a broad range of differentiation capacities. Some of these cells are of a mesenchymal type which can—like their bone marrow (BM) counterpart—support hematopoiesis, since in a previous study we were able to reconstitute lethally irradiated mice by cells isolated from adipose tissue. In the present study, we established that cells derived from the stroma‐vascular fraction of human subcutaneous fat pads support the complete differentiation of hematopoietic progenitors into myeloid and B lymphoid cells. However, these cells are unable to maintain the survival and self‐renewal of hematopoietic stem cells. These features, similar to those of BM adipocytes, are the opposite of those of other cell types derived from mesenchymal progenitors such as BM myofibroblasts or osteoblasts. Because it is abundant and accessible, adipose tissue could be a convenient source of cells for the short‐term reconstitution of hematopoiesis in man. J. Cell. Physiol. 208: 282–288, 2006.

Adipose Tissue as a Dedicated Reservoir of Functional Mast Cell Progenitors

White adipose tissue (WAT) is a heterogeneous tissue, found in various locations throughout the body, containing mature adipocytes and the stroma‐vascular fraction (SVF). The SVF includes a large proportion of immune hematopoietic cells, among which, mast cells that contribute to diet‐induced obesity. In this study, we asked whether mast cells present in mice adipose tissue could derive from hematopoietic stem/progenitor cells (HSPC) identified in the tissue. We therefore performed both in vitro and in vivo experiments dedicated to monitoring the progeny of WAT‐derived HSPC. The entire study was conducted in parallel with bone marrow‐derived cells, considered the gold standard for hematopoietic‐lineage studies. Here, we demonstrate that adipose‐derived HSPC contain a precursor‐cell population committed to the mast cell lineage, and able to efficiently home to peripheral organs such as intestine and skin, where it acquires properties of functional tissue mast cells. Additionally, WAT contains a significant mast cell progenitor population, suggesting that the entire mast cell lineage process take place in WAT. Considering the quantitative importance of WAT in the adult organism and the increasing roles recently assigned to mast cells in physiopathology, WAT may represent an important source of mast cells in physiological and pathological situations. STEM CELLS 2010;28:2065–2072

Human bone marrow adipocytes support complete myeloid and lymphoid differentiation from human CD34+ cells

In humans, the role of bone marrow (BM) adipocytes in supporting haematopoiesis has been questioned. A co‐culture system of CD34+ cells seeded onto either BM undifferentiated mesenchymal stem cells or differentiated adipocytes showed that BM adipocytes did not support the maintenance of immature progenitors but enabled their complete differentiation along the myeloid and lymphoid pathways. These properties appear to be opposite to those of osteoblasts, although both cell types share a common mesenchymal progenitor. These results suggest that stromal cells play a variety of roles in the haematopoietic microenvironment, which could be significant in situations such as osteoporosis or ageing.

Adipose Tissues as Part of the Immune System: Role of Leptin and Cytokines

In addition to its classical role in energy metabolism, there is more and more evidence that adipose tissues could be a player in other physiological processes, including immunity and inflammation. Numerous data have accumulated showing a strong interplay between factors of inflammation (cytokines, adipsin for example) and adipose cells. First, preadipocytes or adipocytes of both peripheral or bone marrow origins are able to synthesise and secrete a variety of inflammatory cytokines. Conversely, some of these factors control adipose cell development and functions. Second, recent papers support the notion that leptin, the main secretory product of adipocytes, is directly involved in the regulation of immune parameters. Even more intriguing is the putative role of leptin in the regulation of hematopoiesis. Third, we have demonstrated that preadipocytes share numerous characteristics with macrophages. Using some of these properties, adipose tissue controls, both directly and indirectly via the brain and the autonomic nervous system, its own development and whole body energy homeostasis.