Date of Award

5-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Bioengineering

Committee Chair/Advisor

Jeremy Mercuri

Committee Member

Brian Booth

Committee Member

Jiro Nagatomi

Committee Member

William Richardson

Abstract

Intervertebral disc degeneration (IVDD) has become increasingly prevalent and is a common contributing factor to low back pain. There are currently no clinical treatment options for IVDD that alleviate the symptoms of IVDD while simultaneously promoting repair of IVD tissue. One treatment option being explored is intradiscal administration of mesenchymal stromal cells (MSCs). However, the microenvironment of the degenerating IVD places significant stress on both native IVD cells and implanted cells. There are several questions that need to be addressed which may help further inform the development of efficacious intradiscal MSC therapies for IVDD. These questions include: 1) Do MSCs derived from different tissue sources respond differently to IVDD-like pH? 2) Does paracrine signaling between MSCs and native nucleus pulposus cells (NPCs) impact their response to IVDD-like pH? The primary findings of this work were that IVDD-like pH negatively affects MSC survival, senescence, and effector function. Furthermore, MSCs derived from different tissue sources respond to low pH in different ways. Additionally, it was found that indirect coculture of MSCs with NPCs resulted in significantly increased MSC survival, matrix production, and an altered cytokine release profile compared to MSCs cultured alone. Finally, this work determined that ASICs are partially responsible for MSC sensing of their local pH as blocking these ion channels significantly increased MSC survival, metabolic activity, matrix production, and growth factor release while significantly decreasing inflammatory cytokine production. Taken together, this research can be used to inform strategies to increase the therapeutic efficacy of MSC-based intradiscal therapies targeting IVDD.

Author ORCID Identifier

0009-0002-1812-3810

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