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Young developmental age cardiac extracellular matrix promotes the expansion of neonatal cardiomyocytes in vitro.

ABSTRACT: A major limitation to cardiac tissue engineering and regenerative medicine strategies is the lack of proliferation of postnatal cardiomyocytes. The extracellular matrix (ECM) is altered during heart development, and studies suggest that it plays an important role in regulating myocyte proliferation. Here, the effects of fetal, neonatal and adult cardiac ECM on the expansion of neonatal rat ventricular cells in vitro are studied. At 24h, overall cell attachment was lowest on fetal ECM; however, ~80% of the cells were cardiomyocytes, while many non-myocytes attached to older ECM and poly-l-lysine controls. After 5 days, the cardiomyocyte population remained highest on fetal ECM, with a 4-fold increase in number. Significantly more cardiomyocytes stained positively for the mitotic marker phospho-histone H3 on fetal ECM compared with other substrates at 5 days, suggesting that proliferation may be a major mechanism of cardiomyocyte expansion on young ECM. Further study of the beneficial properties of early developmental aged cardiac ECM could advance the design of novel biomaterials aimed at promoting cardiac regeneration.

SUBMITTER: Williams C

PROVIDER: S-EPMC3840040 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Young developmental age cardiac extracellular matrix promotes the expansion of neonatal cardiomyocytes in vitro.

Williams C C Quinn K P KP Georgakoudi I I Black L D LD

Acta biomaterialia 20130906 1

A major limitation to cardiac tissue engineering and regenerative medicine strategies is the lack of proliferation of postnatal cardiomyocytes. The extracellular matrix (ECM) is altered during heart development, and studies suggest that it plays an important role in regulating myocyte proliferation. Here, the effects of fetal, neonatal and adult cardiac ECM on the expansion of neonatal rat ventricular cells in vitro are studied. At 24h, overall cell attachment was lowest on fetal ECM; however, ~ ...[more]

PMID: 24012606

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Project description:The transient period of regeneration potential in the postnatal heart suggests molecular changes with maturation influence the cardiac response to damage. We have previously demonstrated that injury and exercise can stimulate cardiomyocyte proliferation in the adult heart suggesting a sensitivity to exogenous signals. Here, we consider whether exogenous fetal ECM and mechanically unloading interstitial matrix can drive regeneration after myocardial infarction (MI) surgery in low-regenerative hearts of day5 mice. Compared to controls, exogenous fetal ECM increases cardiac function and lowers fibrosis at 3 weeks post-injury and this effect can be augmented by softening heart tissue. In vitro experiments support a mechano-sensitivity to exogenous ECM signaling. We tested potential mechanisms and observed that fetal ECM increases nuclear YAP localization which could be enhanced by pharmacological stabilization of the cytoskeleton. Blocking YAP expression lowered fetal ECM effects though not completely. Lastly we observed mechanically unloading heart interstitial matrix increased agrin expression, an extracellular node in the YAP signaling pathway. Collectively, these data support a combined effect of exogenous factors and mechanical activity in altering agrin expression, cytoskeletal remodeling, and YAP signaling in driving cardiomyocyte cell cycle activity and regeneration in postnatal non-regenerative mice. STATEMENT OF SIGNIFICANCE: With the purpose of developing regenerative strategies, we investigate the influence of the local niche on the cardiac injury response. We conclude tissue stiffness, as anticipated in aging or disease, impairs regenerative therapeutics. Most novel, mechanical unloading facilitates enhanced cardiac regeneration only after cells are pushed into a permissive state by fetal biomolecules. Specifically, mechanical unloading appears to increase extracellular agrin expression that amplifies fetal-stimulation of nuclear YAP signaling which correlates with observed increases of cell cycle activity in cardiomyocytes. The results further suggest the cytoskeleton is critical to this interaction between mechanical unloading and independently actived YAP signaling. Using animal models, tissue explants, and cells, this work indicates that local mechanical stimuli can augment proliferating-permissive cardiomyocytes in the natural cardiac niche.

Project description:BackgroundAlthough not fully understood, diabetes mellitus is thought to be associated with cardiac fibrosis and stiffness due to alteration of myocardial extracellular matrix. Newer cardiac magnetic resonance techniques may be able to identify extracellular matrix expansion by measuring extracellular volume fraction (ECV). We used cardiac magnetic resonance to evaluate the association of alteration in the extracellular matrix with diabetic status and its implications on incident heart failure events and all-cause mortality.MethodsWe studied 442 patients who underwent comprehensive contrast cardiac magnetic resonance to assess cardiac morphology and function, left ventricular replacement fibrosis, and pre-post contrast T1 mapping to quantify ECV. The cohort did not have coexisting pathologies associated with ECV alteration. We categorized our final cohort based on diabetic status using criteria from the American Diabetic Association. Subsequent heart failure hospitalization and all-cause death were ascertained.ResultsOur patients were predominantly white with a median age of 57 with 48% being men. Compared with nondiabetes mellitus, diabetes mellitus was significantly associated with elevated ECV after adjusting for clinical and imaging covariates: β coefficient 1.33 (95% CI, 0.22-2.44); P=0.02. Over a median follow-up of 24.5 (interquartile range, 14.8-33.4) months, 52 deaths and 24 heart failure events occurred. Patients with diabetes mellitus and elevated ECV had the worst outcomes compared with patients with diabetes mellitus and normal ECV or nondiabetics. Elevated ECV remained an independent predictor of outcomes (hazard ratio, 3.31 [95% CI, 1.93-5.67]; P<0.001) after adjusting for covariates.ConclusionsElevated ECV is an independent predictor of mortality among patients with diabetes mellitus and may have an additive effect with diabetes mellitus on outcomes. ECV may represent a novel noninvasive biomarker to evaluate severity of diabetic heart disease.

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Young developmental age cardiac extracellular matrix promotes the expansion of neonatal cardiomyocytes in vitro.

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Young developmental age cardiac extracellular matrix promotes the expansion of neonatal cardiomyocytes in vitro.

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