Cell transplantation preserves matrix homeostasis: a novel paracrine mechanism.
OBJECTIVE
Cell transplantation prevents chamber dilatation, but the underlying molecular mechanisms remain undefined. Structural cardiac remodeling involves matrix degradation from an imbalance of matrix metalloproteinases (MMP) relative to endogenous tissue inhibitors of metalloproteinases (TIMP). We aimed to determine the capacity of cell transplantation to alter extracellular matrix in the failing heart and, in so doing, identify novel paracrine molecular mediators underlying the beneficial effects of cell transplantation on chamber dilatation.


METHODS
Smooth muscle cells were transplanted to the dilating left ventricle of cardiomyopathic hamsters (CTX, n = 15) compared with age-matched media-injected cardiomyopathic (CON, n = 15) and normal hamsters (n = 7). After 5 weeks, left ventricular volume was measured by computerized planimetry. Fibrillar collagen was examined by confocal microscopy. Matrix homeostasis was quantified by measuring MMP/TIMP expression/activity relative to myocardial collagen synthesis (14C-proline uptake).


RESULTS
Left ventricular dilatation was attenuated in CTX hearts (P = .02). CTX restored perimysial collagen fiber content and architecture to normal levels. TIMP-2 and TIMP-3 expression were enhanced in CTX (TIMP-2, 195% +/- 42% of CON, P = .02; TIMP-3, 118% +/- 3% of CON, P = .002), and correspondingly, gelatinase MMP-2 activity was reduced (P < .05). The TIMP:MMP ratio was increased in CTX hearts (TIMP-2 to MMP-2, 410% +/- 134% of CON, P = .04, and TIMP-3 to MMP-9, 205% +/- 47% of CON, P = .03), reflecting a reduced capacity for matrix degradation. Collagen synthesis was equivalent (CTX vs CON), suggesting that restored matrix architecture was a function of attenuated matrix degradation.


CONCLUSIONS
These data provide the first evidence that cell transplantation limits ventricular dilatation in the failing heart through a paracrine-mediated mechanism that preserves extracellular matrix homeostasis.
Fedak
Paul W M
PW
Division of Cardiac Surgery, University of Toronto, Toronto General Research Institute, Toronto General Hospital, Toronto, Ontario, Canada. paul.fedak@utoronto.ca
Szmitko
Paul E
PE
Weisel
Richard D
RD
Altamentova
Svetlana M
SM
Nili
Nafiseh
N
Ohno
Nobuhisa
N
Verma
Subodh
S
Fazel
Shafie
S
Strauss
Bradley H
BH
Li
Ren-Ke
RK
D000818:Animals; D009202:Cardiomyopathies / Q000601:surgery*; D017690:Cell Transplantation; D006224:Cricetinae; D005109:Extracellular Matrix / Q000502:physiology*; D006706:Homeostasis; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D009130:Muscle, Smooth / Q000166:cytology*; D019899:Paracrine Communication
D020782:Matrix Metalloproteinases