자료유형  

 학위논문

Control Number  

0016934244

International Standard Book Number  

9798380388924

Dewey Decimal Classification Number  

610

Main Entry-Personal Name  

Collins, Joseph Maurice.

Publication, Distribution, etc. (Imprint  

[S.l.] : University of Pennsylvania., 2023

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2023

Physical Description  

1 online resource(239 p.)

General Note  

Source: Dissertations Abstracts International, Volume: 85-03, Section: B.

General Note  

Advisor: Boerckel, Joel D.;Dyment, Nathaniel A.

Dissertation Note  

Thesis (Ph.D.)--University of Pennsylvania, 2023.

Restrictions on Access Note  

This item must not be sold to any third party vendors.

Summary, Etc.  

요약Endochondral ossification occurs when an initial cartilage template is replaced by co-invading and mutually supportive osteoblast precursors and blood vessels. Osteoblast precursors, in the outer bone collar, coordinate their mobilization into the cartilaginous limb rudiment alongside blood vessel invasion to form the primary ossification center. But how the bone precursor cells mobilize, and direct angiogenesis and subsequent endochondral ossification is unclear. In endochondral bone formation, cellular decisions must integrate both mechanical and morphogenic cues to direct proper transcriptional programs. In fetal development, when the fetus is mechanically constrained (e.g., arthrogryposis caused by a low volume of amniotic fluid), improper mechanical cues can result in skeletal developmental dysplasias. Similarly, in fracture repair, which follows developmental programs, mechanical cues direct the mode of ossification and successful repair. Yet, the how skeletal progenitors integrate mechanical and morphogenic cues to mediate transcription is unclear. The transcriptional regulators Yes-associated protein (YAP) and Transcriptional co-activator with PDZ-binding domain (TAZ) are mechanosensitive, mediate angiogenic gene expression, mediate cell mobilization and their deletion from osteoblast precursors and their progeny is perinatal lethal. Thus, YAP and TAZ are crucially positioned to integrate mechanical and morphogenic cues to mediate endochondral bone development.The goal of this thesis was to define the cellular and mechanical roles of YAP and TAZ in fetal development. Here, we conditionally deleted YAP and TAZ from Osx-expressing cells during fetal development. First, we determined the roles of YAP and TAZ at the tissue level in utero. YAP/TAZ deletion impaired osteogenesis in the primary ossficiation center, hypertrophic cartilage remodeling, and the mobilization of osteoblast precursors into the primary ossification center. Second, we determined the role of YAP and TAZ at the single cell level in utero. We performed extensive single cell RNA sequencing on fetal forelimbs. YAP/TAZ deletion decreased canonical osteogenic genes, such as Bglap, Bglap2, and Spp1, as well as increasing MMP production. Additionally, YAP/TAZ deletion decreased the expression of Cxcl12, which was only uniquely expressed by the vessel-associated osteoblast precursors. YAP/TAZ deletion impaired the cell/cell communication between vessel-associated osteoblast precursors and bone resident endothelial subtypes, through Cxcl12-signaling and extracellular matrix interactions. Lastly, we defined the roles of YAP/TAZ in the mechanoregulation of bone tissue development ex utero. Impairment of YAP/TAZ function both genetic and pharmacological reduced load-induced osteogenesis. Taken together, YAP/TAZ integrate mechanical and morphogenic cues to direct cartilage remodeling, vessel morphogenesis, osteoblast precursor mobilization, and load-induced bone formation. Understanding the transcriptional control and integration of the developmental programs required for fetal development and fracture repair will enable the development of new and potentially less invasive mechanotherapeutic strategies.

Subject Added Entry-Topical Term  

Bioengineering.

Subject Added Entry-Topical Term  

Developmental biology.

Subject Added Entry-Topical Term  

Genetics.

Index Term-Uncontrolled  

Angiogenesis

Index Term-Uncontrolled  

Bone development

Index Term-Uncontrolled  

Mechanobiology

Index Term-Uncontrolled  

Orthopaedic

Added Entry-Corporate Name  

University of Pennsylvania Bioengineering

Host Item Entry  

Dissertations Abstracts International. 85-03B.

Host Item Entry  

Dissertation Abstract International

Electronic Location and Access  

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Control Number  

joongbu:641623