Journal of Molecular Cell Biology Advance Access published online on October 14, 2009
Journal of Molecular Cell Biology, doi:10.1093/jmcb/mjp030
Shifting in Balance Between Osteogenesis and Adipogenesis Substantially Influences Hematopoiesis
1 Stowers Institute for Medical Research, 1000 E. 50th Street, Kansas City, MO 64110 USA
2 Department of Pathology and Laboratory Medicine, Kansas University Medical Center, Kansas City, KS 66160, USA
* Correspondence to: Linheng Li, E-mail: lil{at}stowers.org
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Adipocytes have been viewed as a space-filler in bone marrow for a long time. However, a recent study (Naveiras et al., 2009. Nature 460, 259–263) shows that adipocytes are microenvironmental components that suppress hematopoiesis under homeostatic and especially stressed conditions.
Mesenchymal stem cells are able to give rise to osteoblasts, chondrocytes and adipocytes in bone marrow (Pittenger et al., 1999). Transplantation of mesenchymal stem cells led to improved engraftment of hematopoietic cells, and this implied that differentiated mesenchymal cells in bone marrow support hematopoiesis (Drouet et al., 2005). However, the types of mesenchymal cells and the manner in which they regulate hematopoiesis remain largely unknown. Using genetic approaches such as Bmpr1a and PTH animal models, previous studies have shown that osteoblastic lining cells within the endosteal region play a role in controlling the number of hematopoietic stem cells (HSCs) (Arai et al., 2004; Calvi et al., 2003; Nilsson et al., 2001; Zhang et al., 2003). Another study using Slam markers revealed that endothelial cells form an alternative vasculature niche to maintain HSCs (Kiel et al., 2005). Interestingly in both of the osteoblastic and vascular niches, CXCL12-abundant reticular (CAR) cells were detected (Sugiyama et al., 2006). Another recent study suggested that CAR cells are also of mesenchymal origin (Sacchetti et al., 2007). Real-time imaging with high resolution has recently been used to revisit this question, and researchers observed that osteoblastic (pre-osteoblastic) cells and endothelial cells form a complex network in the endosteal region to support HSCs (Lo Celso et al., 2009; Xie et al., 2009).
It remains unknown whether other types of mesenchymal cells also play a role as microenvironmental components of HSCs. Clinical and experimental observations have revealed a reciprocal relationship between adipocyte differentiation and hematopoiesis in bone marrow (Snyder, 1965). In the bone marrow where active hematopoiesis is taking place, lipid substances are decreased in adipocytes, resulting in ‘red marrow’. In contrast, when hematopoietic tissues are damaged by irradiation or chemotherapeutic drugs, or otherwise impaired during the aging process, adipocytes expand lipid contents, resulting in ‘yellow marrow’. Such myelosuppression seen as yellow marrow has been observed in clinic for many years; consequently, adipocytes were viewed as a ‘space-filler’ (Snyder, 1965).
In their recent study, Naveiras et al. (2009) have revisited this classic question with newly developed technology, including transgenic mice and sophisticated flow cytometry, in order to determine the role of adipocytes in bone marrow.
They compared both the number and function of hematopoietic stem and progenitor cells in adipocyte-rich bone marrow with adipocyte-poor bone marrow in order to identify at which levels adipocytes suppress hematopoiesis. They observed a decrease in absolute number of hematopoietic progenitor cells and a decrease in the relative percentage of HSCs in adipocyte-rich bone marrow. Also, they noted a higher percentage of quiescent CD34-negative HSCs in adipocyte-rich bone marrow. They further asked whether cell-cycle activities of hematopoietic stem and progenitor cells are different between adipocyte-rich bone marrow and adipocyte-poor bone marrow. Interestingly, HSCs did not show a significant difference in their cell-cycle state between the two bone marrow tissues; however, researchers found that hematopoietic progenitor cells were mainly in the G0 phase in adipocyte-rich bone marrow. When comparing only adipocyte-rich and adipocyte-poor bone marrow, it is difficult to conclude whether adipocytes suppress both hematopoietic stem and progenitor cells because other factors in these bone marrow tissues may be responsible. To directly observe the influence of adipocytes on hematopoietic stem and progenitor cells, the researchers utilized a ‘fatless’ mouse model in which adipocyte differentiation was blocked by transgenic expression of a dominant negative form of transcription factor C-EBP
. Since C-EBP is necessary for adipocyte differentiation, these mice could not form adipocytes and therefore were called ‘fatless’. The researchers transplanted bone marrow cells derived from ‘fatless’ mice into wild-type mice and observed expansion of hematopoietic progenitors, but not of HSCs. Furthermore, when the ‘fatless’ donor cells were isolated from the first transplanted wild-type recipients and then retransplanted into wild-type mice (secondary transplantation), more hematopoietic cells were engrafted compared with wild-type donor cells. However, those engrafted cells existed only in short term which means that hematopoietic progenitor cells, not HSCs, were responsible for the increase of engraftment. These observations suggested the negative influence of adipocytes on hematopoietic progenitor cells rather than HSCs. In an in vitro assay, co-culture of purified HSCs with adipocytes differentiated from OP9 bone marrow stromal cells showed an inability to expand hematopoietic cells (CD45+) compared with co-culture with undifferentiated OP9 cells. The result showed that expansion of hematopoietic progenitor cells which derived from HSCs in culture was suppressed in the presence of adipocytes. To test whether or not adipocyte inhibition is cell-contact-dependent, the researchers performed a trans-well chamber experiment. In the chamber, HSCs and adipocytes were physically separated, but soluble factors from both cells could communicate with each other. In this experiment, adipocytes also inhibited the expansion of hematopoietic cells. In order to examine the suppression of hematopoiesis by adipocytes pharmacologically, researchers used bisphenol A diglycidyl ether that inhibits PPAR
activity and thus adipocyte differentiation, and they observed an increase of hematopoietic progenitors. Interestingly, when the ‘fatless’ mice were irradiated, osteogenesis increased, correlating with expansion of hematopoiesis compared with wild-type mice. Thus, adipocytes were shown to actively suppress hematopoiesis rather than passively fill the space left by damaged bone marrow.
From those experiments and observations, the researchers concluded that adipocytes in bone marrow after irradiation suppress expansion of hematopoiesis, primarily by suppressing proliferation of the hematopoietic progenitor cells. However, adipocytes may also maintain quiescent HSCs and this requires further studies.
As shown in recent real-time imaging studies of HSCs in bone marrow ex vivo (Xie et al., 2009) and in vivo (Lo Celso et al., 2009), the hematopoietic microenvironment dynamically changes its function under homeostasis and stressed conditions. In a homeostatic condition, a significant portion of HSCs are maintained in quiescent state, contacting with pre-osteoblasts in the endosteal region of bone surface. Pre-osteoblasts that express N-cadherin may function to maintain HSCs in homeostasis. After irradiation, adipocytes increase lipid components and actively suppress hematopoietic progenitor proliferation. On the other hand, active osteogenesis may favorably promote HSC expansion. Thus shifting of the balance between adipogenesis and osteogenesis imposes different influences on hematopoietic stem and progenitor cells under stresses (Figure 1).
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