De novogeneration of adipocytes from circulating progenitor cells in mouse and human adipose tissue

Abstract

White adipocytes in adults are typically derived from tissue resident mesenchymal progenitors. The recent identification of de novo production of adipocytes from bone marrow progenitor-derived cells in mice challenges this paradigm and indicates an alternative lineage specification that adipocytes exist. We hypothesized that alternative lineage specification of white adipocytes is also present in human adipose tissue. Bone marrow from transgenic mice in which luciferase expression is governed by the adipocyte-restricted adiponectin gene promoter was adoptively transferred to wild-type recipient mice. Light emission was quantitated in recipients by in vivo imaging and direct enzyme assay. Adipocytes were also obtained from human recipients of hematopoietic stem cell transplantation. DNA was isolated, and microsatellite polymorphisms were exploited to quantify donor/recipient chimerism. Luciferase emission was detected from major fat depots of transplanted mice. No light emission was observed from intestines, liver, or lungs. Up to 35% of adipocytes in humans were generated from donor marrow cells in the absence of cell fusion. Nontransplanted mice and stromal-vascular fraction samples were used as negative and positive controls for the mouse and human experiments, respectively. This study provides evidence for a nontissue resident origin of an adipocyte subpopulation in both mice and

The contribution of bone marrow-derived cells to the human adipocyte pool

“…Using bulk preparations of fat cells, the proportion of donor-derived cells in the 2 studies was very similar ranging from 0.1-35% with an average of 5% 37 and 14%, 38 respectively. However, the percentage of BMDCs-derived adipocytes in WAT at a given time point is a rough estimate and does not consider the contribution over the entire life span.…”

“…37,38 Together, the studies included >70 men and women spanning a broad range in body mass index (BMI), thereby enabling an assessment of the possible influence of gender and body fat status on BMDC contribution. The investigators explored donor-and recipient-specific gene sequences within the nuclear DNA (microsatellites and/or single nucleotide polymorphisms) allowing the determination of donor cell infiltration irrespective of gender (of the recipient or donor).…”

“…Moreover, in repeated biopsies from the same subjects, Gavin et al observed an increase in donor-derived fat cells over time. 38 If leukocyte contamination would have been an issue, the proportion of donor-derived sequences would have been independent of time.…”

“…In theory, BMDCs could fuse with recipient cells which after reduction divisions, results in mononuclear cells with heterokaryons containing sequences from both the donor and the recipient. Ploidy analyses of isolated fat cells were performed in the study by Gavin et al 38 Using 2 independent methods, flow cytometry or fluorescence in situ hybridization, they found no evidence of polysomy suggesting that the presence of donorderived adipocytes cannot simply be explained by cell fusion resulting in tetra-or aneuploid cells. Thus, adipocytes with a mixed genetic profile may be generated via more complex mechanisms, e.g.…”

“…42 In accordance with this, bulk preparations of human fat cells from BM-transplanted subjects expressed no detectable amounts of haematopoietic markers. 37,38 Another type of multipotent stem cells are the MSCs which have the capacity to develop into functional cells of the mesenchymal lineage e.g., osteocytes, chondrocytes and adipocytes. 46,47 As MSCs can be found in both BM and PBSC 48,49 it could be speculated that these cells may constitute "adipogenic" BMDCs.…”