Detection of local and remote cellular damage caused by spinal cord and peripheral nerve injury using a heat shock signaling reporter system

Hashimoto-Torii, Kazue; Sasaki, Masanori; Chang, Yu Wen; Hwang, Hye Mee; Waxman, Stephen G.; Kocsis, Jeffery D.; Rakić, Paško; Torii, Masaaki

doi:10.1016/j.ibror.2018.11.003

Cited by 9 publications

(2 citation statements)

References 51 publications

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“…Our previous studies have shown that HSE drives reporter expression not only in the brain but also in many organs and tissues throughout the body of the embryo, including the eyes, heart, lung, and limb bud, in response to prenatal exposure to environmental insults [12]. Detection of cellular damage is also not limited to that of prenatal insults, but includes postnatal insults such as spinal cord or sciatic nerve injury [36]. Therefore, it is expected that these transgenic mice enable long-term tracing of neural as well as non-neural cell lineages affected by various types of chemical, infectious, or physical environmental factors during both prenatal and postnatal periods.…”

Section: Tracing the Lineage Of Cells Prenatally Affected By Environmmentioning

confidence: 99%

Long-term spatial tracking of cells affected by environmental insults

Mohammad

Page

Sasaki

et al. 2020

J Neurodevelop Disord

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Background Harsh environments surrounding fetuses and children can induce cellular damage in the developing brain, increasing the risk of intellectual disability and other neurodevelopmental disorders such as schizophrenia. However, the mechanisms by which early damage leads to disease manifestation in later life remain largely unknown. Previously, we demonstrated that the activation of heat shock (HS) signaling can be utilized as a unique reporter to label the cells that undergo specific molecular/cellular changes upon exposure to environmental insults throughout the body. Since the activation of HS signaling is an acute and transient event, this approach was not intended for long-term tracing of affected cells after the activation has diminished. In the present study, we generated new reporter transgenic mouse lines as a novel tool to achieve systemic and long-term tracking of affected cells and their progeny. Methods The reporter transgenic mouse system was designed so that the activation of HS signaling through HS response element (HSE) drives flippase (FLPo)-flippase recognition target (FRT) recombination-mediated permanent expression of the red fluorescent protein (RFP), tdTomato. With a priority on consistent and efficient assessment of the reporter system, we focused on intraperitoneal (i.p.) injection models of high-dose, short prenatal exposure to alcohol (ethanol) and sodium arsenite (ethanol at 4.0 g/kg/day and sodium arsenite at 5.0 mg/kg/day, at embryonic day (E) 12 and 13). Long-term reporter expression was examined in the brain of reporter mice that were prenatally exposed to these insults. Electrophysiological properties were compared between RFP+ and RFP− cortical neurons in animals prenatally exposed to arsenite. Results We detected RFP+ neurons and glia in the brains of postnatal mice that had been prenatally exposed to alcohol or sodium arsenite. In animals prenatally exposed to sodium arsenite, we also detected reduced excitability in RFP+ cortical neurons. Conclusion The reporter transgenic mice allowed us to trace the cells that once responded to prenatal environmental stress and the progeny derived from these cells long after the exposure in postnatal animals. Tracing of these cells indicates that the impact of prenatal exposure on neural progenitor cells can lead to functional abnormalities in their progeny cells in the postnatal brain. Further studies using more clinically relevant exposure models are warranted to explore this mechanism.

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Section: Tracing the Lineage Of Cells Prenatally Affected By Environmmentioning

confidence: 99%

Long-term spatial tracking of cells affected by environmental insults

Mohammad

Page

Sasaki

et al. 2020

J Neurodevelop Disord

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“…The neuropathological process following SCI is associated with cellular stresses by affecting activation of inflammation, reactive gliosis, and neuronal survival [ 33 ]. Though HSF1 has been shown to be dynamically regulated in the injured cord [ 34 ], its exact roles in the regulation of cell events have not been fully unveiled. Given that endogenous HSF1 is sufficient in inhibiting the expression of inflammatory cytokine TNF-α and IL-1β, the hallmarks of A1 astrocyte secretion [ 4 , 27 , 28 ], it is assumed that HSF1 may act to control reactive astrocyte states following SCI.…”

Section: Introductionmentioning

confidence: 99%

HSF1 is involved in suppressing A1 phenotype conversion of astrocytes following spinal cord injury in rats

et al. 2021

J Neuroinflammation

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Background Two activation states of reactive astrocytes termed A1 and A2 subtypes emerge at the lesion sites following spinal cord injury (SCI). A1 astrocytes are known to be neurotoxic that participate in neuropathogenesis, whereas A2 astrocytes have been assigned the neuroprotective activity. Heat shock transcription factor 1 (HSF1) plays roles in protecting cells from stress-induced apoptosis and in controlling inflammatory activation. It is unknown whether HSF1 is involved in suppressing the conversion of A1 astrocytes following SCI. Methods A contusion model of the rat spinal cord was established, and the correlations between HSF1 expression and onset of A1 and A2 astrocytes were assayed by Western blot and immunohistochemistry. 17-AAG, the agonist of HSF1, was employed to treat the primary cultured astrocytes following a challenge by an A1-astrocyte-conditioned medium (ACM) containing 3 ng/ml of IL-1α, 30 ng/ml of TNF-α, and 400 ng/ml of C1q for induction of the A1 subtype. The effects of 17-AAG on the phenotype conversion of astrocytes, as well as underlying signal pathways, were examined by Western blot or immunohistochemistry. Results The protein levels of HSF1 were significantly increased at 4 days and 7 days following rat SCI, showing colocalization with astrocytes. Meanwhile, C3-positive A1 astrocytes were observed to accumulate at lesion sites with a peak at 1 day and 4 days. Distinctively, the S100A10-positive A2 subtype reached its peak at 4 days and 7 days. Incubation of the primary astrocytes with ACM markedly induced the conversion of the A1 phenotype, whereas an addition of 17-AAG significantly suppressed such inducible effects without conversion of the A2 subtype. Activation of HSF1 remarkably inhibited the activities of MAPKs and NFκB, which was responsible for the regulation of C3 expression. Administration of 17-AAG at the lesion sites of rats was able to reduce the accumulation of A1 astrocytes. Conclusion Collectively, these data reveal a novel mechanism of astrocyte phenotype conversion following SCI, and HSF1 plays key roles in suppressing excessive increase of neurotoxic A1 astrocytes.

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