NJAH, JOEL
(2018)
HARNESSING MESENCHYMAL STEM CELL EXOSOMES AS THERAPY FOR FIBROTIC LUNG DISEASE-INDUCED RIGHT VENTRICULAR DYSFUNCTION.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal disease of unknown etiology with no effective treatment except for lung transplantation. It is characterized by progressive lung fibrosis leading to respiratory failure. Outcomes are worse with comorbidities such as right ventricular systolic dysfunction (RVSD) and pulmonary hypertension (PH). Consequently, there is an urgent need for novel treatment approaches for IPF. This dissertation aims to (1) determine the strength of the association between hemodynamic indices of right ventricular function and survival in IPF, (2) evaluate the therapeutic potential of human bone marrow-derived mesenchymal stem cells (hMSCs) and their derived exosomes in regulating the right ventricular function in a mouse model of IPF, and (3) categorize the protein cargo of hMSCs.
The analysis of the data from an IPF registry showed that the risk of death was significantly higher among subjects with PH in IPF compared to IPF alone (HR: 1.406; 95% CI: 1.026-1.928). Similarly, the risk of mortality was significantly higher in subjects with RVSD compared to those without (HR: 2.523; 95% CI: 1.599-3.979). We concluded that PH and RVSD were strongly associated with survival and that right heart catheterization hemodynamic assessments in IPF is crucial to identify patients at risk of worse outcomes who may be considered for clinical trials.
In evaluating the potential beneficial effects of hMSC and their exosomes in fibrotic lung injuries, we found that the mean pulmonary arterial pressure was significantly increased in the BLM group when compared with controls (20.0±0.45 vs 16.1±0.43, mmHg). Also, there was a significant increase in right ventricular dysfunction (dP/dtmx-EDV) when comparing the BLM group with controls (45.5±2.52 vs 32.8±2.87, mmHg.s-1. ul-1) with an improvement in the RVD after administering hMSCs and exosomes. We concluded that hMSCs and their exosomes have the therapeutic potential to regulate the RV contractile function.
Lastly, we performed a descriptive proteomic analysis to identify and categorize the protein components of the hMSC exosomes. We identified 845 proteins, 166 of them had enzymatic activities involved in proteolysis and oxidative stress regulation. Our conclusion was that the proteome of hMSC exosomes carry enzymatic proteins that could mediate their therapeutic effects.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
4 September 2018 |
| Date Type: |
Publication |
| Defense Date: |
20 July 2018 |
| Approval Date: |
4 September 2018 |
| Submission Date: |
4 September 2018 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
81 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Clinical and Translational Science |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
IPF,bleomycin-induced fibrotic lung injury, registry, survival analysis, proteomic analysis, pulmonary hypertension, right ventricular dysfunction, human MSCs and exosomes. |
| Date Deposited: |
04 Sep 2018 15:39 |
| Last Modified: |
04 Sep 2018 15:39 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/35298 |
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