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Yeh, Shu-Chi

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Yeh

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Shu-Chi

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Yeh, Shu-Chi
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    Postnatal Calvarial Skeletal Stem Cells Expressing PRX1 Reside Exclusively in the Calvarial Sutures and Are Required for Bone Regeneration
    (Elsevier, 2017) Wilk, Katarzyna; Yeh, Shu-Chi; Mortensen, Luke J.; Ghaffarigarakani, Sasan; Lombardo, Courtney M.; Bassir, Seyed Hossein; Aldawood, Zahra; Lin, Charles; Intini, Giuseppe
    Summary Post-natal skeletal stem cells expressing PRX1 (pnPRX1+) have been identified in the calvaria and in the axial skeleton. Here we characterize the location and functional capacity of the calvarial pnPRX1+ cells. We found that pnPRX1+ reside exclusively in the calvarial suture niche and decrease in number with age. They are distinct from preosteoblasts and osteoblasts of the sutures, respond to WNT signaling in vitro and in vivo by differentiating into osteoblasts, and, upon heterotopic transplantation, are able to regenerate bone. Diphtheria toxin A (DTA)-mediated lineage ablation of pnPRX1+ cells and suturectomy perturb regeneration of calvarial bone defects and confirm that pnPRX1+ cells of the sutures are required for bone regeneration. Orthotopic transplantation of sutures with traceable pnPRX1+ cells into wild-type animals shows that pnPRX1+ cells of the suture contribute to calvarial bone defect regeneration. DTA-mediated lineage ablation of pnPRX1+ does not, however, interfere with calvarial development.
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    In Vivo 3D Histomorphometry Quantifies Bone Apposition and Skeletal Progenitor Cell Differentiation
    (Nature Publishing Group UK, 2018) Yeh, Shu-Chi; Wilk, Katarzyna; Lin, Charles; Intini, Giuseppe
    Histomorphometry and Micro-CT are commonly used to assess bone remodeling and bone microarchitecture. These approaches typically require separate cohorts of animals to analyze 3D morphological changes and involve time-consuming immunohistochemistry preparation. Intravital Microscopy (IVM) in combination with mouse genetics may represent an attractive option to obtain bone architectural measurements while performing longitudinal monitoring of dynamic cellular processes in vivo. In this study we utilized two-photon, multicolor fluorescence IVM together with a lineage tracing reporter mouse model to image skeletal stem cells (SSCs) in their calvarial suture niche and analyze their differentiation fate after stimulation with an agonist of the canonical Wnt pathway (recombinant Wnt3a). Our in vivo histomorphometry analyses of bone formation, suture volume, and cellular dynamics showed that recombinant Wnt3a induces new bone formation, differentiation and incorporation of SSCs progeny into newly forming bone. IVM technology can therefore provide additional dynamic 3D information to the traditional static 2D histomorphometry.
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    Live-Animal Imaging of Native Hematopoietic Stem and Progenitor Cells
    (SpringerNature, 2020-02-05) Christodoulou, Constantina; Spencer, Joel; Yeh, Shu-Chi; Turcotte, Raphaele; Kokkaliaris, Konstantinos; Panero, Riccardo; Ramos, Azucena; Guo, Guoji; Seyedhassantehrani, N; Esipova, TV; Vinogradov, SA; Rudzinskas, S; Zhang, Y; Perkins, Archibald; Orkin, Stuart; Calogero, Rafaele; Schroeder, Tim; Lin, Charles; Camargo, Fernando
    The biology of hematopoietic stem cells (HSCs) has predominantly been studied under transplantation conditions. Particularly challenging has been the study of dynamic HSC behaviors in the native niche given that live animal HSC tracking under steady state conditions still represents an elusive goal in the field. Here, we describe a dual genetic strategy in mice that restricts reporter labeling to a subset of the most quiescent longterm HSCs (LT-HSCs) and that is compatible with current intravital imaging approaches in the calvarial marrow. We find that this subset of LT-HSCs resides in an endostealsinusoidal niche where they are simultaneously in close proximity to sinusoidal blood vessels and the endosteal surface. In contrast, multipotent progenitor cells (MPPs) display a broader distance distribution from the endosteum and are more likely to be associated with transition zone vessels. Additionally, our results demonstrate that LTHSCs do not occupy the marrow niches with the deepest hypoxia and that they are found in similar hypoxic environments as MPPs. In vivo time-lapse imaging experiments revealed that LT-HSCs display limited motility compared to the more motile MPPs. However, following activation, LT-HSCs become more motile and expand clonally within spatially restricted domains. These spatial domains have defined characteristics, as HSC expansion is found almost exclusively in a subset of bone marrow cavities exhibiting bone-remodeling activities (resorption and new bone deposition). In contrast, cavities with low bone-resorbing activities do not harbor expanding HSCs. These findings point to a new degree of heterogeneity within the bone marrow microenvironment, imposed by the stages of bone turnover, which has not been recognized previously. Overall, our work describes a model that enables live imaging of LT-HSCs in the native niche and provides insight into the dynamic behaviors of hematopoietic stem and progenitor cells, and the heterogeneity of HSC niches.