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Building bone from blood vesselsEdwin M Horwitz

Mesenchymal stem cells (MSCs) can form different cell types in culture, but their potential to build new tissue in various disorders where tissue is damaged has not been realized. A study now shows how mature cells from blood vessels are a new source of MSCs that may be used to regenerate cartilage and bone (pages 1400–1406).

Edwin M. Horwitz is associate professor of Pediatrics,

Division of Oncology, University of Pennsylvania

School of Medicine, Philadelphia, Pennsylvania, USA,

and attending physician at the Children’s Hospital of

Philadelphia, Philadelphia, Pennsylvania, USA.

e-mail: horwitze@email.chop.edu

Regenerate healthy bone

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Figure 1 Endothelial cell–derived MSCs may be a source of cells for regeneration of bone and cartilage tissues. Vascular endothelial cells expressing high amounts of ALK2 undergo EndMT, giving rise to MSCs in people with FOP. At sites of inflammation, these MSCs differentiate to cartilage-forming chondrocytes, which then undergo endochondral ossification to generate heterotopic bone—a disease hallmark and the cause of morbidity. Medici et al.2 showed that isolated endothelial cells from blood vessels undergo EndMT to form MSCs in vitro after treatment with TGF-β2 or BMP4. These endothelial cell–derived MSCs can differentiate into osteoblasts and chondrocytes in vitro, suggesting that they may be used as cell therapy to regenerate healthy bone after surgical resection of a bone tumor or traumatic injury.

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can differentiate into a spectrum of mes-enchymal tissues, such as bone, cartilage, muscle or tendon—a capacity that could be used as cell therapy to regenerate these tissues3. Subsequent efforts, however, to use MSCs to rebuild host tissues by differentiat-ing them into resident cells have been dis-appointing, and the ‘stemness’ of MSCs is increasingly doubted4—benefits in preclini-cal models or clinical trials have been mostly due to the secretion of soluble mediators5. For example, MSCs improved the outcome of myocardial infarction in mice not by regener-ating cardiomyocytes but rather by secreting TNF-inducible gene-6, an anti-inflammatory protein that reduced infarct size and improved cardiac function6. In the clinic, MSCs can be used to treat graft-versus-host disease after hematopoietic cell transplantation, as they secrete immunosuppressive molecules7.

MSCs are a heterogeneous population of spindle- shaped, plastic-adherent cells that are usually isolated from bone marrow and adipose tissue. But other sources exist, including cord blood, pla-centa and various fetal tissues. The surface pheno-type used to identify MSCs is typically expression of CD105, CD73 and CD90 and the absence of hematopoietic surface markers1. Several inves-tigators have sought to identify a single unique surface antigen to better define MSCs, but such efforts have not been fruitful. The hallmark of MSCs seems to be the capacity to differentiate into osteoblasts, adipocytes and chondrocytes in vitro when they are maintained under the appropriate tissue-specific media conditions. Yet there is no assay to define the function and multipotent capacity of these cells in vivo.

“In the fields of observation, chance favors only the prepared mind”—a famous quote from Louis Pasteur in 1854—emphasizes how some of the most important discoveries in biomedical research began as key observations during studies focused on an entirely differ-ent question. Such may now be the case in the field of MSC therapy. In this issue of Nature Medicine, Medici et al.2, while investigating the pathogenesis of Fibrodysplasia ossificans progressiva (FOP), uncover a new source of MSCs that could revolutionize regenerative medicine for bone and cartilage.

FOP is a severely debilitating disorder caused by an activating mutation in the transforming growth factor-β (TGF-β)/bone morphogenic protein (BMP) type I receptor, activin-like kinase-2 (ALK2), in which acute inflammation causes heterotopic ossification in soft tissues

at virtually any site in the body and for which the source of the ossifying cells was previously unknown. Medici et al.2 showed that bone and cartilage cells from lesions of people with FOP and mice with mutant ALK2 expressed the endothelial markers Tie2 and von Willebrand factor, suggesting an endothelial origin of the ectopic mesenchymal cells that formed the heterotopic tissues (Fig. 1).

Recognizing the potential impact of this find-ing, they showed how human mature endothelial cells treated with BMP4 or TGF-β2 to activate endogenous ALK2 undergo an endothelial to mesenchymal transition (EndMT). The result-ing cells show an MSC surface phenotype and differentiation capacity that may be of use in cell therapy to treat people in need of bone and cartilage regeneration (Fig. 1).

Over the last two decades, the prevailing view was that MSCs are adult stem cells that

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to be demonstrated—then other mesenchymal tissues, such as muscle or tendon, may also be targets for tissue regeneration. Endothelial cells can be easily isolated from animals and human subjects, and the MSC phenotype could be generated, in vitro, by treating endothelial cells with TGF-β2 or BMP4 to induce endo-genous ALK2 activity. The feasibility of initiat-ing preclinical and pilot clinical studies is, thus, already established.

The two most immediate issues, however, are to show that EndMT does not make MSCs more prone to adverse events, such as malig-nant transformation, and to show whether the endothelial-derived MSCs can regenerate a better quality of bone or maybe just regenerate bone faster compared with currently available technologies. This ‘new’ MSC may prove to be an improved MSC and lead to use of MSCs as progenitors to regenerate damaged tissue.

COMPETING FINANCIAL INTERESTS The author declares no competing financial interests.

1. Dominici, M. et al. Cytotherapy 8, 315–317 (2006).2. Medici, D. et al. Nat. Med. 16, 1400–1406 (2010).3. Pittenger, M.F. et al. Science 284, 143–147 (1999).4. Horwitz, E.M. et al. Cytotherapy 7, 393–395 (2005).5. Horwitz, E.M. & Dominici, M. Cytotherapy 10, 771–774

(2008).6. Lee, R.H. et al. Cell Stem Cell 5, 54–63 (2009).7. Ren, G. et al. Cell Stem Cell 2, 141–150 (2008).8. Wagner, W. et al. Exp. Hematol. 33, 1402–1416

(2005).9. Wagner, W. et al. Exp. Hematol. 34, 536–548

(2006).10. Horwitz, E.M. et al. Proc. Natl. Acad. Sci. USA 99,

8932–8937 (2002).11. Méndez-Ferrer, S. et al. Nature 466, 829–834

(2010).12. Crisan, M. et al. Cell Stem Cell 3, 301–313 (2008).13. Lewinson, D. et al. Histochem. Cell Biol. 116, 381–388

(2001).

The findings uncovered in the study by Medici et al.2 could markedly alter our approach to cell therapy. Whereas MSCs derived from bone marrow by adherence to plastic can dif-ferentiate into osteoblasts in vitro, convincing data showing that these MSCs are physiologi-cal osteoprogenitors is still lacking. Instead, these cells seem to mainly support hematopoi-esis11. The isolated and ex vivo–expanded cells accepted as MSCs may in fact represent peri-cytes in situ12.

The robust osteoblast differentiation of MSCs in vitro may be an experimental artifact, and the underlying explanation for the lack of regenerative capacity may be that MSCs do not possess such progenitor potential. In contrast, the MSCs derived from endothelial cells by ALK2-induced EndMT shown by the authors2 give rise to heterotopic bone that can form an ectopic skeleton, showing in situ differentia-tion potential and indicating that they are the basis of diseases such as FOP. Moreover, osteo-blasts and chondrocytes located at bone frac-ture repair sites express endothelial markers13, in contrast to osteoblasts within homeostatic bone, which lack such markers. These obser-vations suggest that endothelial cells may be a physiologic reservoir of EndMT-generated MSCs that differentiate—under the appropri-ate environment cues—to osteoprogenitors and then osteoblasts during physiological stress, such as bone fracture.

The study by Medici et al.2 indicates that endothelial cell–derived MSCs may be superior as a cell source for bone and cartilage cell ther-apy in regenerative medicine. If these MSCs truly have stem-like properties—which has yet

Cells isolated from different tissue sources seem to have different biologic characteris-tics8, which further complicates the evalu-ation of the therapeutic efficacy of MSCs. Additionally, the conditions for the expansion of MSCs ex vivo can substantially affect the final cell product intended for a given thera-peutic application9. Any new source of MSCs or cell expansion protocol therefore requires a specific study to evaluate the capacity of the derived cell to perform the intended function, such as stimulating growth in children with osteogenesis imperfecta10.

Medici et al.2 have identified a new source and processing protocol to generate MSCs. Endothelial cells from people with FOP carry-ing an ALK2 mutation that leads to increased expression and activity of functional ALK2 undergo an EndMT that results in the genera-tion of MSC-like cells. This finding alone is quite interesting, as the current thought is that the end product of EndMT is generic fibro-blasts, which lack the stem cell capacity. In FOP, endothelial-derived MSCs differentiate into cartilage-forming chondrocytes followed by endochondral ossification, presumably under the regulation of inflammatory cyto-kines, as inflammation triggers the formation of heterotopic bone.

Also, the authors showed that ALK2 activation is necessary and sufficient for EndMT2. Using this signaling mechanism, they showed how treating human endothelial cells with TGF-β2 and BMP4—signaling ligands that activate ALK2—could induce EndMT in vitro, generating endothelial-derived MSCs with chondrocyte and osteoblast differentiation potential.

Jeremy F. Reiter is at the Department of

Biochemistry and Biophysics, Cardiovascular

Research Institute, University of California–San

Francisco, San Francisco, California, USA.

e-mail: jeremy.reiter@ucsf.edu

Crippling SWI-SNF makes tumors GLI-ful Jeremy F Reiter

The chromatin remodeling complex SWI-SNF is altered in cancer. New findings now show that the core component SNF5 can block a Hedgehog (Hh) effector, which promotes malignant rhabdoid tumor growth when SNF5 is lost (pages 1429–1433). Targeting this Hh effector may be a way to combat these aggressive childhood tumors.

of nucleosome position is the SWI-SNF complex—originally identified as a regulator of the mating type switch and sucrose fermen-tation in yeast—that affects the transcriptional activity of many genes, either positively or neg-atively. The Drosophila SWI-SNF component, brahma, regulates the activity of homeotic genes, highlighting the conserved role of the SWI-SNF complex among eukaryotes1.

Components of the SWI-SNF nucleosome remodeling complex are also involved in

Most of our DNA is wrapped around histone- based nucleosomes and packaged into chro-matin. Nucleosomes control the access of molecular machines to our DNA, affecting diverse aspects of gene function, such as

replication, repair and transcriptional regu-lation. Given the relevance of chromatin to gene function, it is unsurprising that chro-matin dysregulation contributes to human disease, including cancer. For example, many proteins that either covalently modify histones or interpret these covalent modifications are implicated in oncogenesis.

In addition to modifying histones, changing nucleosome conformation or location regu-lates chromatin function. A crucial regulator

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