Adipose tissue stem cells meet preadipocyte commitment: going back to the future

Abstract

White adipose tissue (WAT) is perhaps the most plastic organ in the body, capable of regeneration following surgical removal and massive expansion or contraction in response to altered energy balance. Research conducted for over 70 years has investigated adipose tissue plasticity on a cellular level, spurred on by the increasing burden that obesity and associated diseases are placing on public health globally. This work has identified committed preadipocytes in the stromal vascular fraction of adipose tissue and led to our current understanding that adipogenesis is important not only for WAT expansion, but also for maintenance of adipocyte numbers under normal metabolic states. At the turn of the millenium, studies investigating preadipocyte differentiation collided with developments in stem cell research, leading to the discovery of multipotent stem cells within WAT. Such adipose tissue-derived stem cells (ASCs) are capable of differentiating into numerous cell types of both mesodermal and nonmesodermal origin, leading to their extensive investigation from a therapeutic and tissue engineering perspective. However, the insights gained through studying ASCs have also contributed to more-recent progress in attempts to better characterize committed preadipocytes in adipose tissue. Thus, ASC research has gone back to its roots, thereby expanding our knowledge of preadipocyte commitment and adipose tissue biology.

Fig. 1.

New adipocyte formation along the vasculature. Transparent chambers were implanted into the ears of live rabbits, allowing visualization of de novo adipocyte formation during tissue revascularization; adipocytes appear as dark outgrowths around the vasculature. The authors of this study (18) observed that “Frequently the fat cells appeared first in close proximity to a blood vessel ... the first fat cells in the right ear (A) appeared beside a vein, later spreading to the tissue between the blood vessels ... Frequently the new fat was first seen in one or two localized regions of the table area and subsequently it gradually spread out from those foci into adjoining regions (B).” This material is reproduced from (18) with permission from John Wiley and Sons, Inc.

Fig. 2.

Relationships between SVCs, ASCs, committed preadipocytes, and mature adipocytes. Typical surface markers and other genes expressed or absent in each cell type are shown. More-extensive lists of surface markers and cell fates are provided, with citations, in Tables 1 (or see supplementary Table I) and 2, respectively. Comparisons of surface markers or other genes differentially expressed between the different cell types reveal potential mechanisms of preadipocyte commitment. Factors that positively regulate preadipocyte commitment are shown in red, and negative regulators are shown in green; effects of PDGF on preadipocyte commitment remain uncertain. Arrows shown as dotted lines designate pathways that are not yet firmly established. For example, whether committed preadipocytes continuously derive from ASCs or merely replenish through autologous self-renewal remains incompletely understood. Equally, whether ASCs or committed preadipocytes can revert to pericytes or ASCs, respectively, requires further investigation. Although mature adipocytes can give rise to other cell types in experimental conditions, the relevance of such trans-differentiation to physiological contexts is not clear. Finally, formation of adipocytes from BM HSCs, fibrocytes, or the neural crest has been reported, so it is possible that ASCs derive from some of these cell types; however, these findings remain controversial.