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      Discovery of a periosteal stem cell mediating intramembranous bone formation

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          Abstract

          Bone is comprised of separate inner endosteal and outer periosteal compartments, each with distinct contributions to bone physiology and each maintaining separate pools of cells due to physical separation by the bone cortex. While the skeletal stem cell giving rise to endosteal osteoblasts has been extensively studied, the identification of a periosteal stem cell has been elusive 15 . Here, we identify a periosteal stem cell (PSC) present in the long bones and calvarium of mice that displays clonal multipotency, self-renewal and sits at the apex of a differentiation hierarchy. Single cell and bulk transcriptional profiling show that PSCs display distinct transcriptional signatures in comparison with both other skeletal stem cells and mature mesenchymal cells. While other skeletal stem cells form bone via an initial cartilage template using the endochondral pathway 4 , PSCs form bone via a direct intramembranous route, providing a cellular basis for the divergence between intramembranous versus endochondral developmental pathways. However there is plasticity in this division, as PSCs acquire endochondral bone formation capacity in response to injury. Genetic blockade of the ability of PSCs to give rise to bone-forming osteoblasts results in selective impairments in cortical bone architecture and defects in fracture healing. A cell analogous to PSCs is present in the human periosteum, raising the possibility that PSCs are attractive targets for drug and cellular therapy for skeletal disorders. Moreover, the identification of PSCs provides evidence that bone contains multiple pools of stem cells, each with distinct physiologic functions.

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          Most cited references22

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          Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment.

          The identity of cells that establish the hematopoietic microenvironment (HME) in human bone marrow (BM), and of clonogenic skeletal progenitors found in BM stroma, has long remained elusive. We show that MCAM/CD146-expressing, subendothelial cells in human BM stroma are capable of transferring, upon transplantation, the HME to heterotopic sites, coincident with the establishment of identical subendothelial cells within a miniature bone organ. Establishment of subendothelial stromal cells in developing heterotopic BM in vivo occurs via specific, dynamic interactions with developing sinusoids. Subendothelial stromal cells residing on the sinusoidal wall are major producers of Angiopoietin-1 (a pivotal molecule of the HSC "niche" involved in vascular remodeling). Our data reveal the functional relationships between establishment of the HME in vivo, establishment of skeletal progenitors in BM sinusoids, and angiogenesis.
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            Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche.

            The repair of injured tendons remains a great challenge, largely owing to a lack of in-depth characterization of tendon cells and their precursors. We show that human and mouse tendons harbor a unique cell population, termed tendon stem/progenitor cells (TSPCs), that has universal stem cell characteristics such as clonogenicity, multipotency and self-renewal capacity. The isolated TSPCs could regenerate tendon-like tissues after extended expansion in vitro and transplantation in vivo. Moreover, we show that TSPCs reside within a unique niche predominantly comprised of an extracellular matrix, and we identify biglycan (Bgn) and fibromodulin (Fmod) as two critical components that organize this niche. Depletion of Bgn and Fmod affects the differentiation of TSPCs by modulating bone morphogenetic protein signaling and impairs tendon formation in vivo. Our results, while offering new insights into the biology of tendon cells, may assist in future strategies to treat tendon diseases.
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              Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts.

              Estrogen prevents osteoporotic bone loss by attenuating bone resorption; however, the molecular basis for this is unknown. Here, we report a critical role for the osteoclastic estrogen receptor alpha (ERalpha) in mediating estrogen-dependent bone maintenance in female mice. We selectively ablated ERalpha in differentiated osteoclasts (ERalpha(DeltaOc/DeltaOc)) and found that ERalpha(DeltaOc/DeltaOc) females, but not males, exhibited trabecular bone loss, similar to the osteoporotic bone phenotype in postmenopausal women. Further, we show that estrogen induced apoptosis and upregulation of Fas ligand (FasL) expression in osteoclasts of the trabecular bones of WT but not ERalpha(DeltaOc/DeltaOc) mice. The expression of ERalpha was also required for the induction of apoptosis by tamoxifen and estrogen in cultured osteoclasts. Our results support a model in which estrogen regulates the life span of mature osteoclasts via the induction of the Fas/FasL system, thereby providing an explanation for the osteoprotective function of estrogen as well as SERMs.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                14 August 2018
                24 September 2018
                October 2018
                24 March 2019
                : 562
                : 7725
                : 133-139
                Affiliations
                [1 ]Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA;
                [2 ]Flow Cytometry, Weill Cornell Medicine, New York, NY, 10065, USA;
                [3 ]Genomics Resources Core Facilities, Weill Cornell Medicine, New York, NY, 10065, USA;
                [4 ]Pathology and Laboratory Medicine Core Facility, Weill Cornell Medicine, New York, NY, 10065, USA;
                [5 ]Department of Medicine, University of Massachusetts Medical School, Worcester, 01655, USA,
                [6 ]Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA;
                [7 ]Orthopaedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA;
                [8 ]Research Division, Hospital for Special Surgery, New York, NY 10021, USA;
                [9 ]Division of Adult Reconstruction and Joint Replacement, Department of Orthopaedic Surgery, Hospital for Special Surgery, New York, NY 10021, USA;
                [10 ]Cancer Genomics and Evolutionary Dynamics at Weill Cornell Medicine, New York, NY, 10065, USA;
                [11 ]Core member, New York Genome Center, New York, NY 10013, USA.
                Author notes

                Author Contributions:

                S.D initiated the study and M.B.G supervised the project. S.D and M.B.G conceived the project. S.D designed, conducted experiments, and analyzed data. A.Y performed all mouse surgeries. J.M supervised flow cytometry. S.L, T.Z and D.A.L performed data analysis on bulk RNA sequencing and Single cell RNA sequencing. R. X., M.E and J.S performed cell culture, quantitative RTPCR, immunostaining and micro CT analysis. N.L, Y.L and Y.Y performed micro-CT, histology and cryo sectioning of samples. M.H, M.P.B and J.H provided access to human samples, helped with sample processing and supervised human studies. S.D and M.B.G prepared the manuscript. All authors read and approved the manuscript.

                Author information:

                S.D is the first author of this paper

                [* ]To whom correspondence should be addressed. Matthew B. Greenblatt, Dept. of Pathology and Laboratory Medicine, Weill Cornell Medical College, 1300 York Ave. LC929a, New York, NY 10065, ( mag3003@ 123456med.cornell.edu )
                Article
                NIHMS1503649
                10.1038/s41586-018-0554-8
                6193396
                30250253
                bb2b752c-be70-43fd-bbd5-d40dfe46652b

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                Uncategorized
                stem cell,bone,periosteum,osteoblasts
                Uncategorized
                stem cell, bone, periosteum, osteoblasts

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