Publication Date

2015-04-29

Availability

Embargoed

Embargo Period

2017-04-28

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Biochemistry and Molecular Biology (Medicine)

Date of Defense

2015-03-25

First Committee Member

Paul C. Schiller

Second Committee Member

Mary L. King

Third Committee Member

Juan Dominguez-Bendala

Fourth Committee Member

Ramiro E. Verdun

Fifth Committee Member

Lina Shehadeh

Abstract

Vascular disease is a leading cause of death worldwide. Vascular repair, essential for tissue maintenance, is critically reduced during vascular disease and aging. Efficient vascular repair requires functional adult stem cells unimpaired by aging or mutation. One protein candidate for reducing stem cell-mediated vascular repair is progerin, a truncated and permanently farnesylated splice variant of lamin A. Progerin expression significantly increases during aging, and is detected in aged, atherosclerotic tissues. Mutations triggering progerin overexpression cause the premature aging disorder Hutchinson-Gilford Progeria Syndrome (HGPS), in which patients die at approximately 13-years of age due to atherosclerosis. Non-specific farnesylation inhibitors are currently in clinical trials for treatment of HGPS. Progerin affects tissues rich in cells derived from mesenchymal stromal cells (MSCs). It has been hypothesized that progerin promotes atherosclerosis by disrupting stem cell functions. Studies using heterogeneous, multipotent MSCs have led to discrepant results. To better understand the mechanisms of progerin expression, we examined exogenous progerin effects using a well-defined, immature, homogeneous subpopulation of MSCs, Marrow Isolated Adult Multilineage Inducible (MIAMI) cells. Progerin decreased cellular proliferation, migration, and self-renewal gene expression. Progerin increased abnormal nuclear morphology, membrane rigidity, and glycolysis. Progerin selectively altered protein expression and subcellular organization, and cytokine secretion; effects on differentiation were inconsistent. Inhibiting farnesylation ameliorated progerin effects on nuclear morphology, proliferation, gene expression, migration, and membrane rigidity, with distinct consequences on cytokine secretion. These results identify novel mechanisms by which progerin alters critical stem cell functions required for tissue repair, offering promising treatment targets for future therapies.

Keywords

Aging; Progerin; Hutchinson-Gilford Progeria Syndrome (HGPS); Mesenchymal Stromal Cells; MIAMI Cells; Adult Stem Cells

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