Human mesenchymal stem cells (MSCs) are multipotent stem cells that differentiate into many of the cells resident in musculoskeletal and stromal tissues of the human body, including fibroblasts, chondrocytes, osteoblasts, myocytes, and adipocytes. While differentiation of the MSCs into appropriate lineages may enhance healing of injured tissues, inappropriate lineage specification may be responsible for numerous pathophysiologic processes, including the decreased bone and increased fat in osteoporotic bones, and the calcification of atherosclerotic vessel walls. Regulation of the lineage commitment of MSCs by local microenvironmental cues therefore may be critical to our fundamental understanding of numerous degenerative as well as healing processes. The long term objective of this research is to characterize the cues within the local surrounding microenvironment that drive the lineage specification and differentiation of human mesenchymal stem cells (MSCs), and the molecular pathways involved. The investigator has discovered that adhesion of MSCs to fibronectin regulates a commitment switch in the MSCs between adipogenic and osteogenic lineage specification, through a mechanism involving RhoA signaling and cytoskeletal tension. During the past grant period, he has demonstrated that these adhesive and mechanical cues specifically regulate SMAD and PPARgamma, two key transcription factors critical to osteogenesis and adipogenesis.
Specific Aim 1 will be to investigate the how integrin activation regulates BMP-SMAD signaling and osteogenesis.
Specific Aim 2 will be to investigate how RhoA regulates SMAD activity.
Specific Aim 3 will be to investigate how adhesive and mechanical cues regulate PPARgamma signaling. Together, these studies will define roles of cell adhesion, RhoA, and cytoskeletal tension in MSC lineage commitment, and establish a molecular basis for the regulation of MSC differentiation by microenvironmental cues.

Public Health Relevance

(PI: Chen)Human mesenchymal stem cells contribute to the maintenance and healing of manymusculoskeletal tissues; but they also can produce inappropriate cell lineages to exacerbatedisease; such as occurs with calcification of atherosclerotic vessels. They are now beingisolated as a promising source of stem cells for regenerative therapies; but again their utilityrests upon predictable control of their differentiation potential. This project is designed todevelop a better understanding of how adhesive and mechanical cues direct these stem cells todifferentiate into specific lineages; such that we may better design future approaches to treat orprevent degenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
7R01GM074048-09
Application #
8839405
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Haynes, Susan R
Project Start
2006-05-01
Project End
2015-04-30
Budget Start
2014-02-01
Budget End
2015-04-30
Support Year
9
Fiscal Year
2013
Total Cost
$303,169
Indirect Cost
$117,971
Name
Boston University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
02215
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Heo, Su-Jin; Driscoll, Tristan P; Thorpe, Stephen D et al. (2016) Differentiation alters stem cell nuclear architecture, mechanics, and mechano-sensitivity. Elife 5:
Cohen, Daniel M; Won, Kyoung-Jae; Nguyen, Nha et al. (2015) ATF4 licenses C/EBP? activity in human mesenchymal stem cells primed for adipogenesis. Elife 4:e06821
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Breckenridge, Mark T; Desai, Ravi A; Yang, Michael T et al. (2014) Substrates with engineered step changes in rigidity induce traction force polarity and durotaxis. Cell Mol Bioeng 7:26-34
Bellas, Evangelia; Chen, Christopher S (2014) Forms, forces, and stem cell fate. Curr Opin Cell Biol 31:92-7
Desai, Ravi A; Rodriguez, Natalia M; Chen, Christopher S (2014) ""Stamp-off"" to micropattern sparse, multicomponent features. Methods Cell Biol 119:3-16
Kim, Iris L; Khetan, Sudhir; Baker, Brendon M et al. (2013) Fibrous hyaluronic acid hydrogels that direct MSC chondrogenesis through mechanical and adhesive cues. Biomaterials 34:5571-80
Legant, Wesley R; Choi, Colin K; Miller, Jordan S et al. (2013) Multidimensional traction force microscopy reveals out-of-plane rotational moments about focal adhesions. Proc Natl Acad Sci U S A 110:881-6

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