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Here we hypothesized that hMSCs pushed through endochondral ossification can engineer a scaled-up ossicle with features of a \u201cbone organ,\u201d including physiologically remodeled bone, mature vasculature, and a fully functional hematopoietic compartment. Engineered hypertrophic cartilage required IL-1\u03b2 to be efficiently remodeled into bone and bone marrow upon subcutaneous implantation. This model allowed distinguishing, by analogy with bone development and repair, an outer, cortical-like perichondral bone, generated mainly by host cells and laid over a premineralized area, and an inner, trabecular-like, endochondral bone, generated mainly by the human cells and formed over the cartilaginous template. Hypertrophic cartilage remodeling was paralleled by ingrowth of blood vessels, displaying sinusoid-like structures and stabilized by pericytic cells. Marrow cavities of the ossicles contained phenotypically defined hematopoietic stem cells and progenitor cells at similar frequencies as native bones, and marrow from ossicles reconstituted multilineage long-term hematopoiesis in lethally irradiated mice. This study, by invoking a \u201cdevelopmental engineering\u201d paradigm, reports the generation by appropriately instructed hMSC of an ectopic \u201cbone organ\u201d with a size, structure, and functionality comparable to native bones. The work thus provides a model useful for fundamental and translational studies of bone morphogenesis and regeneration, as well as for the controlled manipulation of hematopoietic stem cell niches in physiology and pathology.<\/jats:p>","DOI":"10.1073\/pnas.1220108110","type":"journal-article","created":{"date-parts":[[2013,2,11]],"date-time":"2013-02-11T22:48:58Z","timestamp":1360622938000},"page":"3997-4002","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":297,"title":["Engineering of a functional bone organ through endochondral ossification"],"prefix":"10.1073","volume":"110","author":[{"given":"Celeste","family":"Scotti","sequence":"first","affiliation":[{"name":"Departments of Surgery and of Biomedicine, University Hospital Basel, 4056 Basel, Switzerland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elia","family":"Piccinini","sequence":"additional","affiliation":[{"name":"Departments of Surgery and of Biomedicine, University Hospital Basel, 4056 Basel, Switzerland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Takizawa","sequence":"additional","affiliation":[{"name":"Division of Hematology, University Hospital Zurich, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atanas","family":"Todorov","sequence":"additional","affiliation":[{"name":"Departments of Surgery and of Biomedicine, University Hospital Basel, 4056 Basel, Switzerland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Bourgine","sequence":"additional","affiliation":[{"name":"Departments of Surgery and of Biomedicine, University Hospital Basel, 4056 Basel, Switzerland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Papadimitropoulos","sequence":"additional","affiliation":[{"name":"Departments of Surgery and of Biomedicine, University Hospital Basel, 4056 Basel, Switzerland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Barbero","sequence":"additional","affiliation":[{"name":"Departments of Surgery and of Biomedicine, University Hospital Basel, 4056 Basel, Switzerland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus G.","family":"Manz","sequence":"additional","affiliation":[{"name":"Division of Hematology, University Hospital Zurich, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Martin","sequence":"additional","affiliation":[{"name":"Departments of Surgery and of Biomedicine, University Hospital Basel, 4056 Basel, Switzerland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2013,2,11]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1089\/ten.teb.2008.0575"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01657"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0711662105"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1000302107"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2010.01.037"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2474-12-31"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri1779"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09262"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature02040"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature02041"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.08.025"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07547"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-11-389957"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1208384109"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.22203\/eCM.v024a16"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.10435"},{"key":"e_1_3_3_17_2","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1002\/jcb.22538","article-title":"Effect of IL-1beta, PGE(2), and TGF-beta1 on the expression of OPG and RANKL in normal and osteoporotic primary human osteoblasts","volume":"110","author":"Jurado S","year":"2010","unstructured":"S Jurado, et al., Effect of IL-1beta, PGE(2), and TGF-beta1 on the expression of OPG and RANKL in normal and osteoporotic primary human osteoblasts. 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