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Principal Investigator: Matthew Blake Greenblatt
Organization: WEILL MEDICAL COLL OF CORNELL UNIV
Fiscal Year: 2024
Award: $547,424
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
Project Summary
Vertebrae and long bones display marked differences across a range of clinical and basic properties, such as
their basic architecture, responsiveness to PTH, their rate of seeding with solid tumor metastases, or the types
of developmental and degenerative diseases present. The etiology of these differences has remained elusive,
in part due to the current state of skeletal stem cell (SSC) biology that largely considers skeletal stem cells in a
monolithic manner, without drawing clear distinctions in cell type based on bone of origin. Here, we have
identified a vertebral skeletal stem cell (vSSC), having established that it displays a comprehensive set
of stemness features, including the ability to self-renew across multiple rounds of transplantation, the ability
to serially form bone organoids across multiple rounds of transplantation and reisolation, long-term label
retention after a pulse with a chromatin bound H2B-GFP marker, in vivo multipotency through an ability to give
rise to chondrocytes, osteoblasts and adipocyte in vivo, and being long-lived in vivo. This vSSC type is specific
for vertebrae, being completely absent from long bones. These vSSCs have a clear physiologic
contribution to vertebral mineralization, as deleting genes required for osteoblast differentiation with a Zic1-
cre created for this project targeting the lineage of this vSSC produced marked defects in the mineralization of
both the dorsal neural arch and the vertebral body and no detectable phenotype in long bones. Thus, we have
here identified a vSSC, including generating 2 cre lines targeting this cell, that meets all published criteria to be
defined as a novel SSC type. Here, we propose to address a series of key issues enabled by this discovery to
further develop the clinical and physiologic role of this new stem cell type. First, (Aim 1) we will determine the
unique cellular features of the vertebral bone versus long bones, demonstrate which of these features are due
to Zic1+vSSCs, the relationship of Zic1+vSSCs to other skeletal progenitor cell types identified in the literature
and the function of vSSC-specific transcription factors and secreted ligands. Next (Aim 2), we will establish
that this vSSC is a key cell mediating spine fusion, a common orthopedic management strategy to treat a
variety of spine degenerative disorders. Lastly (Aim 3), we will build upon preliminary efforts identifying a
human counterpart of the murine vSSC to fully establish the identity and differentiation hierarchy of the human
vSSC and to determine the functional conservation of vSSC-lineage defining transcription factors. Altogether,
this project will establish the existence and unique properties of a new and distinct vSSC cell type in humans
and mice and facilitate subsequent studies into how this vSSC mediates vertebral skeletal disorders or how
these disorders can be therapeutically addressed by targeting this new stem cell.
Terms: <Address><Adipocytes><Adipose Cell><Alleles><Allelomorphs><Architecture><Automobile Driving><Basal Transcription Factor><Basal transcription factor genes><Binding><Biological><Biology><Bone Formation><CD 200><CD105><CD105 Gene><CD200><Causality><Cell Body><Cell Lineage><Cell surface><Cells><Cellularity><Chondrocytes><Chromatin><Clinical><Data><Defect><Degenerative Disorder><Disease><Disorder><Dorsal><Dysfunction><END Gene><ENG gene><Endoglin Gene><Engineering / Architecture><Etiology><Fat Cells><Functional disorder><Gene Deletion><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genetic><Genetic Transcription><HHT1><HHT1 Gene><Heterograft><Heterologous Transplantation><Human><Label><Ligands><Lipocytes><Literature><Location><Maintenance><Manuscripts><Mature Lipocyte><Mature fat cell><Mediating><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methods><Mice><Mice Mammals><Modern Man><Molecular Interaction><Murine><Mus><Nature><Neoplasm Metastasis><ORW Gene><ORW1><ORW1 Gene><Operative Procedures><Operative Surgical Procedures><Organoids><Orthopedic><Orthopedic Procedures><Orthopedic Surgical Profession><Orthopedics><Osteoblasts><Osteogenesis><Outcome><Phenotype><Physiologic><Physiologic pulse><Physiological><Physiology><Physiopathology><Process><Progenitor Cells><Property><Protein Secretion><Publishing><Pulse><RNA Expression><Reporting><Role><Sampling><Secondary Neoplasm><Secondary Tumor><Series><Shapes><Site><Solid Neoplasm><Solid Tumor><Source><Spinal Column><Spinal Degenerative Disease><Spinal Degenerative Disorder><Spinal Fusion><Spine><Spondylosyndeses><Stem Cell like><Surgical><Surgical Interventions><Surgical Procedure><System><Therapeutic><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Transplantation><Vertebrae><Vertebral><Vertebral Body><Vertebral Bone><Vertebral column><Xenograft><Xenograft procedure><Xenotransplantation><analog><backbone><biologic><bone><bone cell><bone mass><bone tissue formation><bone turnover><cancer metastasis><causation><cell type><degenerative condition><degenerative disease><developmental disease><developmental disorder><disease causation><driving><extremity bone><gene deletion mutation><in vivo><limb bone><long bone><mineralization><mouse model><murine model><neural><novel><osteoblast cell differentiation><osteoblast differentiation><osteoblastic differentiation><pathophysiology><population based><postnatal><progenitor><progenitor biology><progenitor cell biology><progenitor cell niche><progenitor niche><programs><recruit><response><self-renew><self-renewal><skeletal><skeletal disease><skeletal disorder><skeletal progenitor><skeletal progenitor cell><skeletal stem cell><social role><spine bone structure><standard of care><stem><stem and progenitor biology><stem and progenitor cell niche><stem cell biology><stem cell characteristics><stem cell niche><stem cells><stemness><surgery><transcription factor><transplant><tumor><tumor cell metastasis><vertebra body><xeno-transplant><xeno-transplantation>