Transforming blood vessels into bone

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Jun 12, 2010 - 2Department of Developmental Biology; Harvard School of Dental Medicine; Boston, Ma uSa. *Correspondence to: Damian Medici; Email: ...
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Cell Cycle 10:3, 362-363; February 1, 2011; © 2011 Landes Bioscience

Transforming blood vessels into bone Damian Medici1,* and Bjorn R. Olsen2 Division of Matrix Biology; Department of Medicine; Beth Israel Deaconess Medical Center; Harvard Medical School; 2 Department of Developmental Biology; Harvard School of Dental Medicine; Boston, MA USA

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Heterotopic ossification is the process by which bone forms in soft tissues as a result of injury or disease.1 Fibrodysplasia Ossificans Progressiva (FOP) is a rare hereditary disorder in which acute inflammation triggers heterotopic cartilage and bone formation, causing the patients to form an ectopic skeleton and lose the capacity for normal movement.2,3 Chondrogenesis occurs in the early stages of the disease followed by endochondral ossification, the developmental process by which cartilage is replaced by bone.4 Patients with this disease carry a heterozygous activating mutation (R206H) in the gene encoding the signaling receptor ALK2.5 However, little has been known regarding the molecular and cellular mechanism of pathological bone formation in these patients. Where does the ectopic bone come from? Our recent studies6 have shown that the heterotopic cartilage and bone cells are derived from the cells that line the interior of blood vessels, vascular endothelial cells. Lesions in FOP patients contain chondrocytes and osteoblasts that stain positive for endothelial biomarkers. Heterotopic bone from mice expressing a costitutively active ALK2 transgene show identical results. Lineage tracing using a fluorescent endothelial reporter confirmed the endothelial origin of the ectopic bone and cartilage cells.

To assess the cellular effects of the mutated ALK2 gene found in FOP patients, we cloned and implanted the mutant gene into normal vascular endothelial cells. To our surprise, the endothelial cells dramatically changed their morphology from cobblestone-like to spindle-shaped cells, a process known as endothelial-mesenchymal transition (EndMT).7 This process is a normal occurrence during embryonic development, as endothelial cells transform into mesenchymal cells and form connective tissues in the heart known as endocardial cushions.8-10 The spindle-shaped “mesenchymal” (or “fibroblast”) stage has been considered to be the ultimate fate of such transformed endothelial cells. Our data demonstrate that the transformed endothelial cells acquire the anatomical, biochemical and physiological properties of mesenchymal stem cells.11 Endothelial cells induced to undergo EndMT by expression of the mutated ALK2 receptor, or by exogenously activating the normal ALK2 receptor with the recombinant proteins TGFβ2 or BMP4, expressed several biomarkers specific for mesenchymal stem cells. Furthermore, these endothelial-derived mesenchymal stem-like cells could be further differentiated into osteoblasts, chondrocytes or adipocytes when exposed to the appropriate differentiation media (Fig. 1).

This discovery has implications for tissue engineering-based therapy. By replicating the effects of the genetic mutation found in FOP, mature vascular endothelial cells can be converted into various cell types. By mimicking a process that occurs in nature, it is likely to be safer than other methods for reprogramming cells. It also provides a method of tissue engineering that bypasses ethical issues surrounding the direct use of stem cells by differentiating mature vascular endothelial cells into other cell types via a stem-like intermediate. Future studies will identify all potential cell lineages that endothelial cells can be transformed into, and determine whether this endothelial to mesenchymal stem-like cell transition can be induced in vivo for tissue repair or treatment of disease.

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References

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Kaplan FS, et al. Best Pract Res Clin Rheumatol 2008; 22:191-205. 2. Kaplan FS, et al. J Bone Miner Metab 2008; 26:521-30. 3. Shore EM, et al. Bone 2008; 43:427-33. 4. Olsen BR, et al. Ann Rev Cell Dev Biol 2000; 16:191-220. 5. Shore EM, et al. Nat Genet 2006; 38:525-7. 6. Medici D, et al. Nat Med 2010; 16:1400-6. 7. Potenta S, et al. Br J Cancer 2008; 99:1375-9. 8. Lai YT, et al. Dev Biol 2000; 222:1-11. 9. Wang J, et al. Dev Biol 2005; 286:299-310. 10. Azhar M, et al. Dev Dyn 2009; 238:431-42. 11. Chamberlain G, et al. Stem Cells 2007; 25:2739-49.

*Correspondence to: Damian Medici; Email: [email protected] Submitted: 12/06/10; Accepted: 12/07/10 DOI: 10.4161/cc.10.3.14519 Feature on: Medici D, et al. Nat Med 2010; 16:1400-6. 362

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Figure 1. Endothelial cell differentiation in disease and tissue engineering. (A) Schematic representation of the disease process by which blood vessels turn into bone in patients with Fibrodysplasia Ossificans Progressiva. (B) Diagram of endothelial cell plasticity and differentiation in culture for tissue engineering.

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