title: Establishment of bone marrow and hematopoietic niches in vivo by reversion of chondrocyte differentiation of human bone marrow stromal cells.
abstract: Human bone marrow stromal cells (BMSCs, also known as bone marrow-derived "mesenchymal stem cells") can establish the hematopoietic microenvironment within heterotopic ossicles generated by transplantation at non-skeletal sites. Here we show that non-mineralized cartilage pellets formed by hBMSCs ex vivo generate complete ossicles upon heterotopic transplantation in the absence of exogenous scaffolds. These ossicles display a remarkable degree of architectural fidelity, showing that an exogenous conductive scaffold is not an absolute requirement for bone formation by transplanted BMSCs. Marrow cavities within the ossicles include erythroid, myeloid and granulopoietic lineages, clonogenic hematopoietic progenitors and phenotypic HSCs, indicating that complete stem cell niches and hematopoiesis are established. hBMSCs (CD146(+) adventitial reticular cells) are established in the heterotopic chimeric bone marrow through a unique process of endochondral bone marrow formation, distinct from physiological endochondral bone formation. In this process, chondrocytes remain viable and proliferate within the pellet, are released from cartilage, and convert into bone marrow stromal cells. Once explanted in secondary culture, these cells retain phenotype and properties of skeletal stem cells ("MSCs"), including the ability to form secondary cartilage pellets and secondary ossicles upon serial transplantation. Ex vivo, hBMSCs initially induced to form cartilage pellets can be reestablished in adherent culture and can modulate gene expression between cartilage and stromal cell phenotypes. These data show that so-called "cartilage differentiation" of BMSCs in vitro is a reversible phenomenon, which is actually reverted, in vivo, to the effect of generating stromal cells supporting the homing of hematopoietic stem cells and progenitors.
authors.affiliation: Dulbecco Telethon Institute at Tettamanti Research Center, Pediatric Department, University of Milano - Bicocca, Monza, Italy; Tettamanti Research Center, Pediatric Department, University of Milano - Bicocca, San Gerardo Hospital, Monza, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Serafini
authors.affiliation: Stem Cell Lab, Department of Molecular Medicine, Sapienza University of Rome, Italy.
authors.forename: Benedetto
authors.initials: B
authors.lastname: Sacchetti
authors.affiliation: Dulbecco Telethon Institute at Tettamanti Research Center, Pediatric Department, University of Milano - Bicocca, Monza, Italy; Tettamanti Research Center, Pediatric Department, University of Milano - Bicocca, San Gerardo Hospital, Monza, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Pievani
authors.affiliation: Dulbecco Telethon Institute at Tettamanti Research Center, Pediatric Department, University of Milano - Bicocca, Monza, Italy; Tettamanti Research Center, Pediatric Department, University of Milano - Bicocca, San Gerardo Hospital, Monza, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Redaelli
authors.affiliation: Stem Cell Lab, Department of Molecular Medicine, Sapienza University of Rome, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Remoli
authors.affiliation: Tettamanti Research Center, Pediatric Department, University of Milano - Bicocca, San Gerardo Hospital, Monza, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Biondi
authors.affiliation: Stem Cell Lab, Department of Molecular Medicine, Sapienza University of Rome, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Riminucci
authors.affiliation: Stem Cell Lab, Department of Molecular Medicine, Sapienza University of Rome, Italy. Electronic address: paolo.bianco@uniroma1.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bianco
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D002356:Cartilage / Q000166:cytology; D002454:Cell Differentiation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D019902:Chondrocytes / Q000166:cytology*; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D007223:Infant; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D016513:Mice, SCID; D055153:Stem Cell Niche; D055815:Young Adult