University of Michigan
Hox11-Expression Defines a Skeletal Mesenchymal Stem Cell that Contributes to Skeleton Development, Growth, and Repair.
Degree: PhD, Cell and Developmental Biology, 2018, University of Michigan
The skeleton is one of the most widely explored organs for defining mesenchymal stem/progenitor cell (MSC) populations, and there is significant interest in MSCs for their potential in novel and potentially curative therapies for a variety of musculoskeletal disorders. The skeleton is a highly dynamic tissue and MSCs function as a reservoir of new cellular material to support skeletal growth, turnover, and repair. Using a Hoxa11eGFP reporter allele, recent work demonstrated Hox11-expressing cells in the adult skeleton are identified as an MSC-enriched population in the bone marrow and on the cortical bone surfaces. In fact, at all stages examined Hoxa11eGFP-expression is excluded from all differentiated skeletal cell types. Developmentally, Hox genes are critically important patterning regulators and function regionally along the axes of the mammalian skeleton. The Hox11 genes specifically function to pattern the lumbar spine and zeugopod region (radius/ulna and tibia/fibula) of the limb. In addition to classical functions for Hox genes during development, ongoing work has revealed continuing functions for Hox11 during skeletal growth and adult injury repair. Given the continuum of Hox11-expression in undifferentiated stromal cells and the genetic evidence for Hox11 function at all stages, I investigated the possibility that Hox11-expression may identify a skeletal progenitor population throughout the life of the animal. These studies aimed to understand the lineage-relationship of Hox11-expressing stromal cells from embryonic to adult stages and to test the skeletal progenitor potential of this population over time.
The first evidence to support the hypothesis that Hox11-expressing cells are skeletal progenitors at all stages, was flow cytometry data demonstrating that Hoxa11eGFP-expressing cells co-express adult MSC markers PDGFRα/CD51 and Leptin Receptor (LepR) throughout life, beginning from embryonic stages. To rigorously investigate the skeletal progenitor potential of this population in vivo, I generated a Hoxa11-CreERT2 allele by Cas9/CRISPR genetic engineering. I demonstrate that Hoxa11-lineage marked cells are multi-potent in vivo and contribute to all mesenchymal cell types of the skeleton; cartilage, bone, and adipose. Hoxa11-lineage marked cells continue to contribute to new skeletal cells out to at least one year of age. In addition to giving rise to the skeleton, Hoxa11-lineage marked stromal cells persist within the bone marrow and on the bone surfaces throughout life, even from embryonic stages. Lineage-marked stromal cells co-express MSC markers PDGFRα/CD51 and LepR and continue to express Hoxa11eGFP at all time points. The expression of Hoxa11eGFP within Hoxa11-lineage marked MSCs throughout life, and the continuous contribution to new skeletal cells provides evidence that Hox11-expressing MSCs are self-renewing skeletal stem cells. These data reconcile conflicting reports in the field regarding when MSCs arise and provide definitive genetic evidence for an embryonic, perichondrial origin for…
Advisors/Committee Members: Spence, Jason (committee member), Allen, Benjamin (committee member), Lin, Jiandie (committee member), Lucas-Alcaraz, Daniel (committee member), Wellik, Deneen Marie (committee member).
Subjects/Keywords: Hox genes; skeleton stem cell; mesenchymal stem/stromal cell (MSC); skeletal patterning; lineage-trace; developmental biology; Molecular, Cellular and Developmental Biology; Science
to Zotero / EndNote / Reference
APA (6th Edition):
Pineault, K. (2018). Hox11-Expression Defines a Skeletal Mesenchymal Stem Cell that Contributes to Skeleton Development, Growth, and Repair. (Doctoral Dissertation). University of Michigan. Retrieved from http://hdl.handle.net/2027.42/147658
Chicago Manual of Style (16th Edition):
Pineault, Kyriel. “Hox11-Expression Defines a Skeletal Mesenchymal Stem Cell that Contributes to Skeleton Development, Growth, and Repair.” 2018. Doctoral Dissertation, University of Michigan. Accessed January 26, 2020.
MLA Handbook (7th Edition):
Pineault, Kyriel. “Hox11-Expression Defines a Skeletal Mesenchymal Stem Cell that Contributes to Skeleton Development, Growth, and Repair.” 2018. Web. 26 Jan 2020.
Pineault K. Hox11-Expression Defines a Skeletal Mesenchymal Stem Cell that Contributes to Skeleton Development, Growth, and Repair. [Internet] [Doctoral dissertation]. University of Michigan; 2018. [cited 2020 Jan 26].
Available from: http://hdl.handle.net/2027.42/147658.
Council of Science Editors:
Pineault K. Hox11-Expression Defines a Skeletal Mesenchymal Stem Cell that Contributes to Skeleton Development, Growth, and Repair. [Doctoral Dissertation]. University of Michigan; 2018. Available from: http://hdl.handle.net/2027.42/147658