Matrix Metalloproteinase 9 Secreted by Hypoxia Cardiac Fibroblasts Triggers Cardiac Stem Cell Migration <i>In Vitro</i>

Gao, Qing; Guo, Maojuan; Zeng, Wenyun; Wang, Yijing; Yang, Lin; Pang, Xiaoli; Li, Huhu; Suo, Yanrong; Jiang, Xijuan; Yu, Chunquan

doi:10.1155/2015/836390

Cited by 18 publications

(15 citation statements)

References 37 publications

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“…These observations suggest that while MAPK subfamilies do serve as important regulators of VEGF production, they are not involved in stiffness-mediated changes in MAPK pathway signaling. Further, VEGF expression was found to increase with increased hydrogel modulus; interestingly, while hypoxia is known to elevate VEGF production in human cardiac and adventitial fibroblasts [49, 50], the hydrogels in our studies exhibited similar swelling capacities, upwards of 97%, corresponding to similar pore sizes (13.1–15.2 nm), as calculated using the Flory-Rehner equation (Table S1). Thus, diffusional limitations were similar across gel formulations, and any differences in local pO 2 levels were unlikely to be related to diffusion.…”

Section: Discussionsupporting

confidence: 67%

Aortic adventitial fibroblast sensitivity to mitogen activated protein kinase inhibitors depends on substrate stiffness

et al. 2017

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Adventitial fibroblasts (AFs) are key determinants of arterial function and critical mediators of arterial disease progression. The effects of altered stiffness, particularly those observed across individuals during normal vascular function, and the mechanisms by which AFs respond to altered stiffness, are not well understood. To study the effects of matrix stiffness on AF phenotype, cytokine production, and the regulatory pathways utilized to interpret basic cell-matrix interactions, human aortic AFs were grown in 5%, 7.5%, and 10% (w/v%) PEG-based hydrogels with Young’s moduli of 1.2, 3.3, and 9.6 kPa, respectively. In 5% gels, AFs had higher proliferation rates, elevated monocyte chemoattractant protein-1 secretion, and enhanced monocyte recruitment. Significantly more AFs were α-smooth muscle actin positive in 7.5% gels, indicating myofibroblast development. AFs in 10% gels had low proliferation rates but produced high levels of interleukin-6 and vascular endothelial growth factor-A. Importantly, these modulus-dependent changes in AF phenotype were accompanied by alterations in the mitogen-activated protein kinase (MAPK) pathways contributing to the production of cytokines. These data indicate that complex cell regulatory changes occur with altered tissue stiffness and suggest that therapeutics affecting MAPK pathways may have altered effects on AFs depending on substrate stiffness.

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Section: Discussionsupporting

confidence: 67%

Aortic adventitial fibroblast sensitivity to mitogen activated protein kinase inhibitors depends on substrate stiffness

et al. 2017

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“…2b), in comparison to the levels of cell-secreted MMPs in in vitro cell cultures ( e.g. , 1–500 ng/mL)[43, 44]. Within the 2-week in vitro study period, cell-induced degradation of 16 kPa and 9 kPa hydrogels led to macroscopically intact tissue constructs, while the 2 kPa group showed some evidence of degradation, forming macroscopic pores within the constructs (Fig.…”

Section: Discussionmentioning

confidence: 99%

Contractile force generation by 3D hiPSC-derived cardiac tissues is enhanced by rapid establishment of cellular interconnection in matrix with muscle-mimicking stiffness

et al. 2017

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Engineering 3D human cardiac tissues is of great importance for therapeutic and pharmaceutical applications. As cardiac tissue substitutes, extracellular matrix-derived hydrogels have been widely explored. However, they exhibit premature degradation and their stiffness is often orders of magnitude lower than that of native cardiac tissue. There are no reports on establishing interconnected cardiomyocytes in 3D hydrogels at physiologically-relevant cell density and matrix stiffness. Here we bioengineer human cardiac microtissues by encapsulating human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in chemically-crosslinked gelatin hydrogels (1.25×108/mL) with tunable stiffness and degradation. In comparison to the cells in high stiffness (16 kPa)/slow degrading hydrogels, hiPSC-CMs in low stiffness (2 kPa)/fast degrading and intermediate stiffness (9 kPa)/intermediate degrading hydrogels exhibit increased intercellular network formation, α-actinin and connexin-43 expression, and contraction velocity. Only the 9 kPa microtissues exhibit organized sarcomeric structure and significantly increased contractile stress. This demonstrates that muscle-mimicking stiffness together with robust cellular interconnection contributes to enhancement in sarcomeric organization and contractile function of the engineered cardiac tissue. This study highlights the importance of intercellular connectivity and physiologically-relevant cell density and matrix stiffness to best support 3D cardiac tissue engineering.

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“…MMP activity is regulated by α-2-M and TIMPs. MMP-2 is a proteolytic enzyme, especially secreted under hypoxic conditions, that increases the number of migrating progenitor cells, particularly cardiac stem cells, to damaged tissue 32 , 33 . TIMP-1 inhibits most MMPs, with high affinity for MMP-9, which is released a few hours after a MI 34 .…”

Section: Discussionmentioning

confidence: 99%

Unravelling the effects of mechanical physiological conditioning on cardiac adipose tissue-derived progenitor cells in vitro and in silico

Llucià‐Valldeperas

Bragós

Soler‐Botija

et al. 2018

Sci Rep

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Mechanical conditioning is incompletely characterized for stimulating therapeutic cells within the physiological range. We sought to unravel the mechanism of action underlying mechanical conditioning of adipose tissue-derived progenitor cells (ATDPCs), both in vitro and in silico. Cardiac ATDPCs, grown on 3 different patterned surfaces, were mechanically stretched for 7 days at 1 Hz. A custom-designed, magnet-based, mechanical stimulator device was developed to apply ~10% mechanical stretching to monolayer cell cultures. Gene and protein analyses were performed for each cell type and condition. Cell supernatants were also collected to analyze secreted proteins and construct an artificial neural network. Gene and protein modulations were different for each surface pattern. After mechanostimulation, cardiac ATDPCs increased the expression of structural genes and there was a rising trend on cardiac transcription factors. Finally, secretome analyses revealed upregulation of proteins associated with both myocardial infarction and cardiac regeneration, such as regulators of the immune response, angiogenesis or cell adhesion. To conclude, mechanical conditioning of cardiac ATDPCs enhanced the expression of early and late cardiac genes in vitro. Additionally, in silico analyses of secreted proteins showed that mechanical stimulation of cardiac ATDPCs was highly associated with myocardial infarction and repair.

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Matrix Metalloproteinase 9 Secreted by Hypoxia Cardiac Fibroblasts Triggers Cardiac Stem Cell Migration In Vitro

Cited by 18 publications

References 37 publications

Aortic adventitial fibroblast sensitivity to mitogen activated protein kinase inhibitors depends on substrate stiffness

Aortic adventitial fibroblast sensitivity to mitogen activated protein kinase inhibitors depends on substrate stiffness

Contractile force generation by 3D hiPSC-derived cardiac tissues is enhanced by rapid establishment of cellular interconnection in matrix with muscle-mimicking stiffness

Unravelling the effects of mechanical physiological conditioning on cardiac adipose tissue-derived progenitor cells in vitro and in silico

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