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Thrombin Preconditioning Enhances Therapeutic Efficacy of Human Wharton's Jelly-Derived Mesenchymal Stem Cells in Severe Neonatal Hypoxic Ischemic Encephalopathy.

ABSTRACT: We investigated whether thrombin preconditioning of human Wharton's jelly-derived mesenchymal stem cells (MSCs) improves paracrine potency and thus the therapeutic efficacy of naïve MSCs against severe hypoxic ischemic encephalopathy (HIE). Thrombin preconditioning significantly enhances the neuroprotective anti-oxidative, anti-apoptotic, and anti-cytotoxic effects of naïve MSCs against oxygen-glucose deprivation (OGD) of cortical neurons in vitro. Severe HIE was induced in vivo using unilateral carotid artery ligation and hypoxia for 2 h and confirmed using brain magnetic resonance imaging (MRI) involving >40% of ipsilateral hemisphere at postnatal day (P) 7 in newborn rats. Delayed intraventricular transplantation of 1 × 105 thrombin preconditioned but not naïve MSCs at 24 h after hypothermia significantly enhanced observed anti-inflammatory, anti-astroglial, and anti-apoptotic effects and the ensuing brain infarction; behavioral tests, such as cylinder rearing and negative geotaxis tests, were conducted at P42. In summary, thrombin preconditioning of human Wharton's jelly-derived MSCs significantly boosted the neuroprotective effects of naïve MSCs against OGD in vitro by enhancing their anti-oxidative, anti-apoptotic, and anti-cytotoxic effects, and significantly attenuated the severe HIE-induced brain infarction and improved behavioral function tests in vivo by maximizing their paracrine anti-inflammatory, anti-astroglial, and anti-apoptotic effects.

SUBMITTER: Kim YE

PROVIDER: S-EPMC6566845 | biostudies-other | 2019 May

REPOSITORIES: biostudies-other

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Thrombin Preconditioning Enhances Therapeutic Efficacy of Human Wharton's Jelly-Derived Mesenchymal Stem Cells in Severe Neonatal Hypoxic Ischemic Encephalopathy.

Kim Young Eun YE Sung Se In SI Chang Yun Sil YS Ahn So Yoon SY Sung Dong Kyung DK Park Won Soon WS

International journal of molecular sciences 20190520 10

We investigated whether thrombin preconditioning of human Wharton's jelly-derived mesenchymal stem cells (MSCs) improves paracrine potency and thus the therapeutic efficacy of naïve MSCs against severe hypoxic ischemic encephalopathy (HIE). Thrombin preconditioning significantly enhances the neuroprotective anti-oxidative, anti-apoptotic, and anti-cytotoxic effects of naïve MSCs against oxygen-glucose deprivation (OGD) of cortical neurons in vitro. Severe HIE was induced in vivo using unilateral ...[more]

PMID: 31137455

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Project description:Interferon regulatory factor 4 (IRF4), a transcription factor recognized as a key regulator of lymphoid and myeloid cell differentiation, has recently been recognized as a critical mediator of macrophage activation. Previously we have reported that IRF4 signaling is closely correlated with anti-inflammatory polarization of microglia in adult mice after stroke. However, IRF4's role in the inflammatory response in the immature brain is unknown. Using a model of neonatal hypoxic ischemic encephalopathy (HIE) we investigated the regulatory action of IRF4 signaling in the activation of microglia and monocytes after HIE. IRF4 myeloid cell conditional knockout (CKO) postnatal day 10 (P10) male pups were subjected to a 60-min hypoxic-ischemic insult by the Rice-Vanucci model (RVM). IRF4 gene floxed mice (IRF4fl/fl) were used as controls. Brain atrophy and behavioral deficits were measured 7 days after HIE. Flow cytometry (FC) was performed to examine central (microglial activation) and peripheral immune cell responses by both cell membrane and intracellular marker staining. Serum levels of cytokines were determined by ELISA. The results showed that IRF4 CKO pups had increased tissue loss and worse behavioral deficits than IRF4fl/fl mice seven days after HIE. FC demonstrated significantly more infiltration of monocytes and neutrophils in the ischemic brains of IRF4 CKO vs IRF4fl/fl pups. IRF4 CKO ischemic microglia were more pro-inflammatory as evidenced by higher expression of the pro-inflammatory marker CD68, and increased intracellular TNF? and IL-1? levels compared to controls. In addition, IRF4 deletion from myeloid cells resulted in increased levels of circulating pro-inflammatory cytokines and higher endothelial MMP9 expression after HIE. These data indicate that IRF4 signaling in myeloid cells plays a regulatory role in neuroinflammation and that deletion of myeloid IRF4 is detrimental to HIE injury, suggesting that IRF4 could serve as a potential therapeutic target for neonatal ischemic brain injury.

Dataset Information

Thrombin Preconditioning Enhances Therapeutic Efficacy of Human Wharton's Jelly-Derived Mesenchymal Stem Cells in Severe Neonatal Hypoxic Ischemic Encephalopathy.

Publications

Thrombin Preconditioning Enhances Therapeutic Efficacy of Human Wharton's Jelly-Derived Mesenchymal Stem Cells in Severe Neonatal Hypoxic Ischemic Encephalopathy.

Similar Datasets

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