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Senescent Cells with Augmented Cytokine Production for Microvascular Bioengineering and Tissue Repairs.

ABSTRACT: Controlled delivery of cytokines and growth factors has been an area of intense research interest for molecular and cellular bioengineering, immunotherapy, and regenerative medicine. In this study, we show that primary human lung fibroblasts chemically induced to senescence (cell cycle arrest) can act as a living source to transiently produce factors essential for promoting vasculogenesis or angiogenesis, such as VEGF, HGF, and IL-8. Co-culture of senescent fibroblasts with HUVECs in a fibrin gel demonstrated accelerated formation and maturation of microvessel networks in as early as three days. Unlike the usage of non-senescent fibroblasts as the angiogenesis-promoting cells, this approach eliminates drawbacks related to the overproliferation of fibroblasts and the subsequent disruption of tissue architecture, integrity, or function. Co-culture of pancreatic islets with senescent fibroblasts and endothelial cells in a gel matrix maintains the viability and function of islets ex vivo for up to five days. Applying senescent fibroblasts to wound repair in vivo led to increased blood flow in a diabetic mouse model. Together, this work points to a new direction for engineering the delivery of cytokines and growth factors that promote microvascular tissue engineering and tissue repairs.

SUBMITTER: Xiao Y

PROVIDER: S-EPMC7141414 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Senescent Cells with Augmented Cytokine Production for Microvascular Bioengineering and Tissue Repairs.

Xiao Yang Y Liu Chang C Chen Zhuo Z Blatchley Michael R MR Kim Dongjoo D Zhou Jing J Xu Ming M Gerecht Sharon S Fan Rong R

Advanced biosystems 20190527 8

Controlled delivery of cytokines and growth factors has been an area of intense research interest for molecular and cellular bioengineering, immunotherapy, and regenerative medicine. In this study, we show that primary human lung fibroblasts chemically induced to senescence (cell cycle arrest) can act as a living source to transiently produce factors essential for promoting vasculogenesis or angiogenesis, such as VEGF, HGF, and IL-8. Co-culture of senescent fibroblasts with HUVECs in a fibrin ge ...[more]

PMID: 32270028

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Project description:ObjectivesCatecholaminergic vasopressors are the cornerstone of circulatory shock management. Nevertheless, catecholamines have problematic side effects, arousing a growing interest in noncatecholaminergic agents such as vasopressin or angiotensin-II. However, their respective effects on sepsis-associated microvascular endothelial dysfunction such as permeability or inflammation remain elusive. We investigated the role of catecholamines and other vasopressors on Toll-like receptor agonists-induced microvascular endothelial permeability and inflammation.SettingUniversity research laboratory/cell research.SubjectsHuman pulmonary microvascular endothelial cells from multiple donors.InterventionConfluent monolayers of human pulmonary microvascular endothelial cells were treated with Toll-like receptor agonists (lipopolysaccharide, Poly[I:C], or tripalmitoyl-S-glyceryl cysteine) in the presence or absence of epinephrine, norepinephrine, vasopressin, and angiotensin-II. Permeability was inferred from transendothelial resistance, measured using electrical cell impedance sensing, where decreased transendothelial resistance is consistent with increased permeability. Cell-cell junction molecule expression was assessed via immunofluorescence microscopy and flow cytometry. We quantified cytokines in supernatants of Toll-like receptor agonist-treated human pulmonary microvascular endothelial cells.Measurements and main resultsEpinephrine and norepinephrine both ameliorate lipopolysaccharide, polyinosinic:polycytidylic acid, or tripalmitoyl-S-glyceryl cysteine-induced reductions in transendothelial resistance, a surrogate for endothelial permeability. In contrast, the noncatecholaminergic agents, vasopressin, and angiotensin-II did not affect Toll-like receptor agonists-induced reductions in transendothelial resistance. β1- and β2-adrenergic receptor antagonists reduced the effects of the catecholamines on transendothelial resistance, whereas α-adrenergic receptor antagonists did not. We observed that epinephrine and norepinephrine induced actin cytoskeletal rearrangement and normalized the membrane expression of proteins involved with adherens-junctions (vascular endothelial-cadherin) and tight-junctions (zona occludens-1). Despite having a substantial effect on endothelial permeability, epinephrine and norepinephrine did not affect human pulmonary microvascular endothelial cell survival or production of interleukin-8, interleukin-6, or monocyte chemoattractant protein-1 (CCL-2) induced by Toll-like receptor agonists, suggesting that these functions are regulated separately from permeability.ConclusionsOur findings demonstrate that treatment with epinephrine or norepinephrine strongly reduces endothelial permeability induced by agonists of multiple Toll-like receptors (Toll-like receptor-2, Toll-like receptor-3, Toll-like receptor-4) in vitro. Our studies suggest that both β1- and β2-adrenergic receptors mediate the stabilizing effects of epinephrine and norepinephrine on the endothelial barrier.

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Senescent Cells with Augmented Cytokine Production for Microvascular Bioengineering and Tissue Repairs.

Publications

Senescent Cells with Augmented Cytokine Production for Microvascular Bioengineering and Tissue Repairs.

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