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reports: Wei Tang, Daniel Zeve, Jae Myoung Suh, Darko Bosnakovski, Michael Kyba, Robert E. Hammer, Michelle D. Tallquist, and Jonathan M. Graff White Fat Progenitor Cells Reside in the Adipose Vasculature Science 2008; 322: 583-586 [Abstract] [Full text] [PDF]

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Response to R. P. Erickson's E-Letter

Wei Tang, Daniel Zeve, Jae Myoung Suh, Darko Bosnkovski, Michael Kyba, Robert E. Hammer, Michelle D. Tallquist, Jonathan M. Graff   (12 January 2009)

Origin of Adipocytes

Robert P. Erickson   (12 January 2009)

Response to R. P. Erickson's E-Letter 12 January 2009
Wei Tang Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA, Daniel Zeve, Jae Myoung Suh, Darko Bosnkovski, Michael Kyba, Robert E. Hammer, Michelle D. Tallquist, Jonathan M. Graff Respond to this E-Letter: Re: Response to R. P. Erickson's E-Letter	Adipose tissue is highly dynamic, growing and shrinking in response to various cues, of which dietary stimuli have drawn the most attention. These and other data indicated the presence of a long hypothesized adipogenic stem cell (1, 2). We recently identified such an adipose stem cell by creating and characterizing mice that express molecular reporters in the adipose lineage (Reports, "White fat progenitor cells reside in the adipose vasculature," by W. Tang et al., 24 October 2008, p. 583; published online 18 September 2008). Remarkably, the adipose stem cells reside as mural cells (pericytes) embedded within the walls of vessels located in adipose depots (3). Mural cells are present in both blood and lymphatic vessels (4, 5). R. P. Erickson raises the important possibility that the identified adipose stem cells could be located in either or both types of vessels. Erickson refers to some of the reports suggesting that lymphatic function can regulate fat formation and an even greater body of literature supports an adipose stem cell niche situated within blood vessels (6–10). However, the data in support of either of these possibilities are indirect, and in large part not directed towards this question, which in our and Dr. Erickson's view remains incompletely defined. Our general sense is that at least some, and likely most, of the progenitors are located in mural compartment of blood vessels. For example, the number and density of pericytes present in the majority of vessels in which we have imaged the adipose stem cells seems much higher than is characteristic of lymphatic vessels and is more consistent with a blood vessel niche (11). Further, some of the stem-cell containing vessels are surrounded by adventitia, which given their caliber more likely identifies them as blood vessels. Also, many of the relevant vessels are filled with red blood cells, another important discriminator. These data do not exclude the possibility that a portion of adipose progenitors are also allocated to lymph vessels. To more directly examine this question, we attempted immunohistochemical approaches with lymph vessel markers and antibody-stained adipose tissues using indirect immuno-fluorescence for the lymph markers (e.g., LYVE-1) and direct fluorescence to identify GFP-labeled adipose stem cells, however no adipose stem cells were present in the lymph vessels expressing these markers. In summary, we agree with Erickson that a subset of adipose stem cells could reside in the wall of lymph vessels. Our in vivo, histological, immunological, and cell marking data, indicate that most, and likely the significant majority, of the adipose stem cells are present in blood vessels. Definitive assessment of this question will require the generation of new tools to examine pericyte lineage, lymphatic specification, and the lineage relationships between pericytes, lymphatics, and blood vessels. Wei Tang, Daniel Zeve, Jae Myoung Suh, Darko Bosnkovski, Michael Kyba Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Robert E. Hammer Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Michelle D. Tallquist Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Jonathan M. Graff Department of Developmental Biology, Department of Molecular Biology, and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. References 1 G. J. Hausman, D. R. Campion, R. J. Martin, J. Lipid Res. 21, 657 (1980). 2. G. Ailhaud, P. Grimaldi, R. Negrel, Annu. Rev. Nutr. 12, 207 (1992). 3. W. Tang et al., Science 322, 583 (2008). 4. T. V. Petrova et al., Nat. Med. 10, 974 (2004). 5. A. Armulik, A. Abramsson, C. Betsholtz, Circ. Res. 97, 512 (2005). 6. S. Cinti, M. Cigolini, O. Bosello, P. Bjorntorp, J. Submicrosc. Cytol. 16, 243 (1984). 7. L. Napolitano, J. Cell Biol. 18, 663 (1963). 8. S. Nishimura et al., Diabetes 56, 1517 (2007). 9. M. A. Rupnick et al., Proc. Natl. Acad. Sci. USA 99, 10730 (2002). 10. M. G. Kolonin, P. K. Saha, L. Chan, R. Pasqualini, W. Arap, Nat. Med. 10, 625 (2004). 11. R. H. Adams, K. Alitalo, Nat. Rev. Mol. Cell Biol. 8, 464 (2007).
Origin of Adipocytes 12 January 2009
Robert P. Erickson Department of Pediatrics, University of Arizona, Tucson, Arizona 85724-5073, USA Respond to this E-Letter: Re: Origin of Adipocytes	W. Tang, et al.'s finding that pericytes are precursors of white fat adipocytes (Reports, "White fat progenitor cells reside in the adipose vasculature," 24 October 2008, p. 583; published online 18 September 2008) raises the question as to whether they are from the blood vasculature, lymph vasculature or both. Since "only a subset of mural cells within a vessel" met criteria for a precursor (1) and PDGFRβ marks mural cells of both vasculature types (2), the possibility of a lymphatic source is germane. Studies on FOXC2 also suggest this possibility. FOXC2 was implicated in lymphatic development when it was found that haploinsufficiency of FOXC2 caused the syndrome of lymphedema-distichiasis (3). The phenotype includes an increased number and dilated lymphatics in a man (4) and mice (5). These changes are secondary to an increased number of pericytes which may inhibit valve formation (6). This increase in pericytes is associated with an increase in brown fat (5) and it has been found that FOXC2 is expressed in this type of fat (7). There are a number of associations between lymphatic and fat abnormalities (particularly lipodystrophy) in which it would be interesting to know if the number of adipocytes has increased or whether the existing ones have been stimulated to grow. Over-expression of FOXC2 in white and brown adipose tissues using the aP2 fat-specific promoter decreased intra-abdominal white fat, increased brown fat, and led to insulin resistance (8). Mice haploinsufficient for Prox1, an initiator of lymphatic development, also develop obesity, perhaps because of leakage of lymph into the interstitium (9). Thus, the source and number of pericyte precursors is important for many problems in lymphedema, obesity, diabetes and related disorders. Robert P. Erickson Department of Pediatrics, University of Arizona, Tucson, Arizona 85724-5073, USA. References 1. W. Tang et al., Science 322, 583 (2008). 2. R. Cao et al., Cancer Cell 6, 333 (2004). 3. J. Fang et al., Am. J. Hum. Genet. 67, 1382 (2000). 4. J. B. Kinmonth, Proc. R. Soc. Med. 65, 721 (1972). 5. B. M. Kriederman et al., Hum. Mol. Genet. 12, 1179 (2003). 6. T. V. Petrova et al., Nat. Med. 10, 974 (2004). 7. S. L. Dagenais et al., Gene Expr. Patterns 4, 611 (2004). 8. A. Cederberg et al., Cell 106, 563 (2001). 9. N. L. Harvey et al., Nat. Genet. 37, 1072 (2005).