Non-Regenerative Benefits of Adult Bone Marrow Derived Stem Cells for Myocardial Protection
Abstract
Ischaemic heart disease is the most common cause of mortality in the
western hemisphere and it is rapidly becoming the leading cause of death
globally. Moreover, therapeutic interventions by cardiologists and cardiac
surgeons frequently subject the heart to acute I/R injury, which in itself can
cause mortality.
Recent investigations of adult stem cells have primarily focused on their
regenerative potential for chronic ischaemic heart disease. In this thesis, I
have investigated the hypothesis that adult bone marrow derived stem cells
are cardioprotective in acute regional myocardial I/R injury. In a rat model
of left anterior descending coronary artery (LAD) reversible occlusion and
reperfusion, I demonstrate that an intravenous bolus of adult bone marrow
derived (1) bone marrow mononuclear (BMNNC) and (2) mesenchymal
stem cells (MSC) upon reperfusion can attenuate infarct size. This effect is
comparable to ischaemic preconditioning (IPC), which is the gold standard
for cardioprotection.
Next, I demonstrated the mechanisms for adult stem cell
cardioprotection are principally anti-apoptotic and depend upon stem cell
secreted factors to (1) activate phosphatidylinositide 3-kinase (PI3)/Akt cell
survival kinase-signaling pathway (2) inhibit glycogen synthase kinase-3β
(3) inhibit p38MAPK (4) inhibit nuclear translocation of p65NF-κB.
7
Proteomic analysis of myocardium subjected to I/R and treated with either
BMMNC or BMMNC derived supernatant (BMS) upon reperfusion
demonstrated higher expression of a whole host of pro-survival proteins.
These were notably (1) 14-3-3-ε protein (2) anti-oxidant peroxiredoxin-6 (3)
heat shock protein (HSP) αB-crystallin, HSP72, HSP tumour necrosis factor
receptor-1 associated protein, and HSP ischaemia responsive protein-94 (4)
glycolytic protein glyceraldehyde-3-phosphate dehydrogenase (5)
mitochondrial aconitase and mitochondrial voltage-dependent anionselective
channel protein-1.
Thereafter, I investigated the mobilization of endogenous bone marrow
stem cells and trafficking to the ischaemic myocardium by stromal cell
derived factor-1 (SDF-1) /chemokine, receptor type 4 (CXCR4) signaling. I
demonstrate high up-regulated expression of CXCR4 and CD26 in
BMMNC following IPC, which might have a role in IPC-mediated
cardioprotection. Finally, and in concordance with this finding I
demonstrate that both IPC and an exogenous MSC bolus upon reperfusion
can synergize to abolish acute myocardial I/R injury.
Authors
Yasin, MohammedCollections
- Theses [3834]