Abstract
Kinins are endogenous, biologically active peptides released into the plasma and tissues via the kallikrein-kinin system in several pathophysiological events. Among kinins, bradykinin (BK) is widely distributed in the periphery and brain. Several studies on the neuro-modulatory actions of BK by the B2BK receptor (B2BKR) indicate that this neuropeptide also functions during neural fate determination. Previously, BK has been shown to induce differentiation of nerve-related stem cells into neuron cells, but the response in mature brain astrocytes is unknown. Herein, we used rat brain astrocyte (RBA) to investigate the effect of BK on cell transdifferentiation into a neuron-like cell morphology. Moreover, the signaling mechanisms were explored by zymographic, RT-PCR, Western blot, and immunofluorescence staining analyses. We first observed that BK induced RBA transdifferentiation into neuron-like cells. Subsequently, we demonstrated that BK-induced RBA transdifferentiation is mediated through B2BKR, PKC-δ, ERK1/2, and MMP-9. Finally, we found that BK downregulated the astrocytic marker glial fibrillary acidic protein (GFAP) and upregulated the neuronal marker neuron-specific enolase (NSE) via the B2BKR/PKC-δ/ERK pathway in the event. Therefore, BK may be a reprogramming factor promoting brain astrocytic transdifferentiation into a neuron-like cell, including downregulation of GFAP and upregulation of NSE and MMP-9 via the B2BKR/PKC-δ/ERK cascade. Here, we also confirmed the transdifferentiative event by observing the upregulated neuronal nuclear protein (NeuN). However, the electrophysiological properties of the cells after BK treatment should be investigated in the future to confirm their phenotype.
Highlights
IntroductionIn the central nervous system (CNS), neuronal differentiation of stem cells normally results from a gradually progressive restriction in developmental potential and is regulated by specific and temporally precise genetic events [2]
We were surprised to find that treatment of rat brain astrocytes (RBA) with
Theimage imagerepresents represents one one of Astrocytes,aa glial glial cell, cell, are it isit is Astrocytes, are broadly broadlydistributed distributedthroughout throughoutthe the well known that astrocytes have multiple effects on physiological and pathological well known that astrocytes have multiple effects on central nervous system (CNS) physiological and pathological processes, including maintaining homeostasis, providing neurotrophins, and regulating processes, including maintaining homeostasis, providing neurotrophins, and regulating neural signal transmission [5,32,33,34]
Summary
In the central nervous system (CNS), neuronal differentiation of stem cells normally results from a gradually progressive restriction in developmental potential and is regulated by specific and temporally precise genetic events [2]. This gradually progressive neural induction and neuronal differentiation have been demonstrated in vitro in embryonic stem (ES) cells, adult neural stem cells, or bone. Specific molecular control mechanisms determine the differentiation of totipotent ES cells into neural stem cells that can undergo self-renewal and generate more restricted precursors in response to different factors. Restricted precursors can differentiate into all cells within the nervous system, including neurons and glia [2,3]. We explored whether matured brain astrocytes have the potential to be transdifferentiated into neurons
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