Adipose Tissue-Derived Mesenchymal Stem Cells Facilitate Hematopoiesis in Vitro and in Vivo : Advantages Over Bone Marrow-Derived Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) have emerged as a new therapeutic modality for reconstituting the hematopoietic microenvironment by improving engraftment in stem cell transplantation. However, the availability of conventional bone marrow (BM)-derived MSCs (BMSCs) is limited. Recent studies showed that a large number of MSCs can be easily isolated from fat tissue (adipose tissue-derived MSCs [ADSCs]). In this study, we extensively evaluated the hematopoiesis-supporting properties of ADSCs, which are largely unknown. In vitro coculture and progenitor assays showed that ADSCs generated significantly more granulocytes and progenitor cells from human hematopoietic stem cells (HSCs) than BMSCs. We found that ADSCs express the chemokine CXCL12, a critical regulator of hematopoiesis, at levels that are three fold higher than those with BMSCs. The addition of a CXCL12 receptor antagonist resulted in a lower yield of granulocytes from ADSC layers, whereas the addition of recombinant CXCL12 to BMSC cocultures promoted the growth of granulocytes. In vivo cell homing assays showed that ADSCs facilitated the homing of mouse HSCs to the BM better than BMSCs. ADSCs injected into the BM cavity of fatally irradiated mice reconstituted hematopoiesis more promptly than BMSCs and subsequently rescued mice that had received a low number of HSCs. Secondary transplantation experiments showed that ADSCs exerted favorable effects on long-term HSCs. These results suggest that ADSCs can be a promising therapeutic alternative to BMSCs.Hematopoiesis is a dynamic process that involves self-renewal of hematopoietic stem cells in the bone marrow, generation of lineage-committed cells, and mobilization of mature cells into the bloodstream. Mesenchymal stem cells (MSCs) present in bone marrow (BM) are thought to give rise to cells that constitute the hematopoietic microenvironment. MSCs produce a number of cytokines and extracellular matrix proteins and express cell adhesion molecules, all of which are involved in the regulation of hematopoiesis.¹ Human MSCs, when injected into the bone marrow cavity of nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice, differentiate into pericytes, myofibroblasts, BM stromal cells, bone osteocytes, bone-lining osteoblasts, and endothelial cells, which constitute the functional components of the hematopoietic microenvironment.² In recent studies, cotransplantation of human MSCs and HSCs resulted in increased chimerism or accelerated hematopoietic recovery (or both) in animal models and in humans.^3,4,5,6All of the above studies used bone marrow-derived MSCs (BMSCs). However, there are several drawbacks in the use of BMSCs for clinical application, including the fact that they are only available in limited number even though large quantities of infused cells are required for treatment. In addition, there is a possibility that BMSCs might be contaminated with malignant cells when they are harvested from patients with a hematological malignancy (eg, leukemia). The discoveries that a large number of nonadipocyte stem cells exist in fat tissue (adipose tissue-derived MSCs [ADSCs]) and that these cells can be rapidly expanded ex vivo, suggested that ADSCs might be useful for clinical applications.⁷ Recent studies showed that ADSCs are a viable alternative to BMSCs for treatment of animal models of various kinds of diseases.^8,9,10,11,12 However, it has been reported that even though ADSCs and BMSCs are very similar, ADSCs are not completely identical to BMSCs.^13,14 To date, little is known concerning the ability of ADSCs to support hematopoiesis. We therefore extensively examined the hematopoiesis-supporting properties of ADSCs in vitro and in vivo and report that ADSCs possess several advantages over BMSCs.