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746 results on '"Mohamed, Fatma A."'

5. A multi-stem cell basis for craniosynostosis and calvarial mineralization.

Author

Bok, Seoyeon, Yallowitz, Alisha, Sun, Jun, McCormick, Jason, Cung, Michelle, Hu, Lingling, Lalani, Sarfaraz, Li, Zan, Sosa, Branden, Baumgartner, Tomas, Byrne, Paul, Zhang, Tuo, Morse, Kyle, Mohamed, Fatma, Ge, Chunxi, Franceschi, Renny, Cowling, Randy, Greenberg, Barry, Pisapia, David, Imahiyerobo, Thomas, Lakhani, Shenela, Ross, M, Hoffman, Caitlin, Debnath, Shawon, and Greenblatt, Matthew

Subjects
Humans, Mice, Animals, Craniosynostoses, Osteogenesis, Cell Lineage, Phenotype, Stem Cells
Abstract

Craniosynostosis is a group of disorders of premature calvarial suture fusion. The identity of the calvarial stem cells (CSCs) that produce fusion-driving osteoblasts in craniosynostosis remains poorly understood. Here we show that both physiologic calvarial mineralization and pathologic calvarial fusion in craniosynostosis reflect the interaction of two separate stem cell lineages; a previously identified cathepsin K (CTSK) lineage CSC1 (CTSK+ CSC) and a separate discoidin domain-containing receptor 2 (DDR2) lineage stem cell (DDR2+ CSC) that we identified in this study. Deletion of Twist1, a gene associated with craniosynostosis in humans2,3, solely in CTSK+ CSCs is sufficient to drive craniosynostosis in mice, but the sites that are destined to fuse exhibit an unexpected depletion of CTSK+ CSCs and a corresponding expansion of DDR2+ CSCs, with DDR2+ CSC expansion being a direct maladaptive response to CTSK+ CSC depletion. DDR2+ CSCs display full stemness features, and our results establish the presence of two distinct stem cell lineages in the sutures, with both populations contributing to physiologic calvarial mineralization. DDR2+ CSCs mediate a distinct form of endochondral ossification without the typical haematopoietic marrow formation. Implantation of DDR2+ CSCs into suture sites is sufficient to induce fusion, and this phenotype was prevented by co-transplantation of CTSK+ CSCs. Finally, the human counterparts of DDR2+ CSCs and CTSK+ CSCs display conserved functional properties in xenograft assays. The interaction between these two stem cell populations provides a new biologic interface for the modulation of calvarial mineralization and suture patency.

Published
2023

18. Control of craniofacial development by the collagen receptor, discoidin domain receptor 2

Author

Mohamed, Fatma F, Ge, Chunxi, Hallett, Shawn A, Bancroft, Alec C, Cowling, Randy T, Ono, Noriaki, Binrayes, Abdul-Aziz, Greenberg, Barry, Levi, Benjamin, Kaartinen, Vesa M, and Franceschi, Renny T

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Pediatric, Pediatric Research Initiative, Congenital Structural Anomalies, Dental/Oral and Craniofacial Disease, Underpinning research, 1.1 Normal biological development and functioning, Musculoskeletal, Animals, Humans, Mice, Cartilage, Chondrocytes, Collagen, Discoidin Domain Receptor 2, Receptors, Collagen, craniofacial growth, extracellular matrix, synchondrosis, cranial suture, Mouse, cell biology, developmental biology, mouse, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Development of the craniofacial skeleton requires interactions between progenitor cells and the collagen-rich extracellular matrix (ECM). The mediators of these interactions are not well-defined. Mutations in the discoidin domain receptor 2 gene (DDR2), which encodes a non-integrin collagen receptor, are associated with human craniofacial abnormalities, such as midface hypoplasia and open fontanels. However, the exact role of this gene in craniofacial morphogenesis is not known. As will be shown, Ddr2-deficient mice exhibit defects in craniofacial bones including impaired calvarial growth and frontal suture formation, cranial base hypoplasia due to aberrant chondrogenesis and delayed ossification at growth plate synchondroses. These defects were associated with abnormal collagen fibril organization, chondrocyte proliferation and polarization. As established by localization and lineage-tracing studies, Ddr2 is expressed in progenitor cell-enriched craniofacial regions including sutures and synchondrosis resting zone cartilage, overlapping with GLI1 + cells, and contributing to chondrogenic and osteogenic lineages during skull growth. Tissue-specific knockouts further established the requirement for Ddr2 in GLI +skeletal progenitors and chondrocytes. These studies establish a cellular basis for regulation of craniofacial morphogenesis by this understudied collagen receptor and suggest that DDR2 is necessary for proper collagen organization, chondrocyte proliferation, and orientation.

Published
2023

31. The collagen receptor, discoidin domain receptor 2, functions in Gli1-positive skeletal progenitors and chondrocytes to control bone development

Author

Mohamed, Fatma F, Ge, Chunxi, Cowling, Randy T, Lucas, Daniel, Hallett, Shawn A, Ono, Noriaki, Binrayes, Abdul-Aziz, Greenberg, Barry, and Franceschi, Renny T

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Osteoporosis, Stem Cell Research, Stem Cell Research - Nonembryonic - Non-Human, 2.1 Biological and endogenous factors, Underpinning research, Aetiology, 1.1 Normal biological development and functioning, Musculoskeletal, Clinical sciences
Abstract

Discoidin Domain Receptor 2 (DDR2) is a collagen-activated receptor kinase that, together with integrins, is required for cells to respond to the extracellular matrix. Ddr2 loss-of-function mutations in humans and mice cause severe defects in skeletal growth and development. However, the cellular functions of Ddr2 in bone are not understood. Expression and lineage analysis showed selective expression of Ddr2 at early stages of bone formation in the resting zone and proliferating chondrocytes and periosteum. Consistent with these findings, Ddr2+ cells could differentiate into hypertrophic chondrocytes, osteoblasts, and osteocytes and showed a high degree of colocalization with the skeletal progenitor marker, Gli1. A conditional deletion approach showed a requirement for Ddr2 in Gli1-positive skeletal progenitors and chondrocytes but not mature osteoblasts. Furthermore, Ddr2 knockout in limb bud chondroprogenitors or purified marrow-derived skeletal progenitors inhibited chondrogenic or osteogenic differentiation, respectively. This work establishes a cell-autonomous function for Ddr2 in skeletal progenitors and cartilage and emphasizes the critical role of this collagen receptor in bone development.

Published
2022

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