Growth and Remodeling of Extracellular Matrix During Limb Development

Yue Leng, Purdue University

Abstract

Within the cellular microenvironment, the extracellular matrix (ECM) is an essential support structure that provides dynamic signaling cues through biochemical and physical factors. In response to interactions with the ECM, cells activate biochemical and mechanotransduction pathways that modulate their survival, migration, proliferation, differentiation, and function. Recent studies suggest the utility of ECM molecules as a basis for engineered scaffolds to restore functionality to damaged or missing tissues. However, current designs have poor functional outcomes. A reason engineered scaffolds have not been able to adequately restore the damaged tissue is that the scaffold design predominantly relies upon artificial polymers and/or ECM components that mimic the architecture and composition of the homeostatic adult tissue. Meanwhile, researchers investigating the mechanism of tissue formation and regeneration have primarily focused on the transcription factors and growth factor-induced signaling pathways controlling cell behaviors. What has yet to be fully taken into consideration by tissue engineers is that the composition and mechanics of ECM undergoes dramatical remodeling during development and scar-free repair, which plays a significant role in directing cellular behavior in the formation of mature functional tissue. Here, we focus on the musculoskeletal system, and the hypothesis driving this research is that an ECM-based template is crucial for the functional muscle formation during vertebrate forelimb development. To test our hypothesis, we first evaluate how hyaluronic acid, a main skeletal muscle ECM component, regulates myogenesis. Secondly, we investigate the musculoskeletal ECM as a whole using clearing methods to see how the ECM template guides the muscle fiber alignment and growth in the murine developing forelimb. Third, we develop a multiscale computational model to help characterize macroscale growth and remodeling which is driven by microscale ECM remodeling processes. Taken together, a better understanding of the synergistic biochemical and biomechanical interactions between cells and the ECM will provide critical insight into the mechanisms that orchestrate tissue assembly and establish guidelines for regenerative therapies.

Degree

Ph.D.

Advisors

Calve, Purdue University.

Subject Area

Biomechanics|Artificial intelligence|Cellular biology|Mechanics|Medicine|Morphology

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