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L8. Cell Transplantation Preserves Matrix Homeostasis:
A Novel Paracrine Mechanism
Paul W.M. Fedak, Paul Szmitko, Richard D. Weisel, Svetlana M. Altamentova, Subodh Verma, Shafie Fazel, Bradley H. Strauss, Ren-ke Li; Toronto, ON, Canada
Objective:
Cell transplantation prevents heart failure but the underlying molecular mechanisms remain undefined. Progressive cardiac remodeling and failure involves extracellular matrix degradation from an imbalance of matrix metalloproteinases (MMPs) relative to their endogenous tissue inhibitors (TIMPs). We aimed to determine the capacity of cell transplantation to alter matrix remodeling in the failing heart and in so doing, identify novel paracrine molecular mediators underlying the beneficial effects of cell transplantation on LV remodeling.
Methods:
Smooth muscle cells (SMC) were transplanted by single LV epicardial injection in cardiomyopathic hamsters (CTX, n=15) before significant LV dilatation as compared to age-matched media-injected cardiomyopathic (CON, n=15) and normal hamsters (NOR, n=7). After 5 weeks, LV volume was measured by computerized planimetry. The integrity of the fibrillar collagen matrix was examined by confocal microscopy. Matrix homeostasis was quantified by measuring MMP/TIMP expression/activity (immunoblotting and gelatin zymography) relative to myocardial collagen synthesis (14C-proline uptake).
Results:
Cardiomyopathy (CON vs NOR) was associated with progressive LV dilatation and excessive matrix turnover as evidenced by increased MMP activity, reduced TIMP expression, perimysial collagen fiber degradation, and increased collagen synthesis (all P<0.05). Engrafted SMC were identified in CTX hearts at 5 weeks. LV dilatation was attenuated in CTX hearts (CTX vs CON, 76±14 vs 97±16 μL, P=0.02). Cell transplantation restored perimysial collagen fiber content and organization to normal levels (CTX vs CON: 3.3±0.2% vs 1.3±0.1% collagen area, P=0.001, increased length and diameter, P<0.01). TIMP-2 and TIMP-3 expression was enhanced in CTX (TIMP-2, 195±42% of CON, P=0.02; TIMP-3, 118±3% of CON, P=0.002) and correspondingly, gelatinase MMP-2 activity was reduced compared to CON (P<0.05). The ratio of matrix inhibitors to proteolytic enzymes was profoundly increased in cell transplanted hearts (TIMP-2 to MMP-2, 410±134% of CON, P=0.04 and TIMP-3 to MMP-9, 205±47% of CON, P=0.03), reflecting a reduced capacity for matrix degradation. Collagen synthesis was not significantly different (CTX vs CON) suggesting that restored matrix architecture was a function of attenuated matrix degradation.
Conclusions:
These data provide the first evidence that CTX limits cardiac dilatation by preserving extracellular matrix homeostasis. A paracrine-mediated attenuation of matrix degradation is an important contributing mechanism by which CTX preserves cardiac structure and function. Gene-enhanced cell transplantation with specific TIMPs may optimize the ability of engrafted cells to attenuate maladaptive remodeling and the progression to heart failure.
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