Thyroid Hormone and Neural Stem Cells: Repair Potential Following Brain and Spinal Cord Injury

Abstract

Neurodegenerative diseases are characterized by chronic neuronal and/or glial cell loss, while traumatic injury is often accompanied by the acute loss of both. Multipotent neural stem cells (NSCs) in the adult mammalian brain spontaneously proliferate, forming neuronal and glial progenitors that migrate toward lesion sites upon injury. However, they fail to replace neurons and glial cells due to molecular inhibition and the lack of pro-regenerative cues. A major challenge in regenerative biology therefore is to unveil signaling pathways that could override molecular brakes and boost endogenous repair. In physiological conditions, thyroid hormone (TH) acts on NSC commitment in the subventricular zone, and the subgranular zone, the two largest NSC niches in mammals, including humans. Here, we discuss whether TH could have beneficial actions in various pathological contexts too, by evaluating recent data obtained in mammalian models of multiple sclerosis (MS; loss of oligodendroglial cells), Alzheimer's disease (loss of neuronal cells), stroke and spinal cord injury (neuroglial cell loss). So far, TH has shown promising effects as a stimulator of remyelination in MS models, while its role in NSC-mediated repair in other diseases remains elusive. Disentangling the spatiotemporal aspects of the injury-driven repair response as well as the molecular and cellular mechanisms by which TH acts, could unveil new ways to further exploit its proregenerative potential, while TH (ant)agonists with cell type-specific action could provide safer and more target-directed approaches that translate easier to clinical settings.

Developmental thyroid disruption permanently affects the neuroglial output in the murine subventricular zone

“…We subsequently investigated whether postnatal TH deficiency disrupts SVZ organization and, therefore, neuroglial processes. We focused on the neuron/glia balance because T 3 -TRα1 represses Sox2 to favor neuronal commitment in adult NSCs and progenitors ( López-Juárez et al., 2012 ) and because this readout is a relevant indicator of how well NSC/progenitors might respond to brain injury ( Vancamp et al., 2020a ). qPCR and RNAscope data showed downregulated expression of markers associated with neuroglial commitment as well as the TH target genes Klf9 and Dio3 as a response to low intracellular T 3 .…”

“…These questions are central in stem cell biology because SVZ NSCs are an endogenous source of new neurons and glia that could facilitate CNS injury repair ( Vancamp et al., 2020a ). Additionally, mounting evidence shows that developmental exposure to endocrine-disrupting chemicals (EDCs) that alter TH homeostasis ( Boas et al., 2012 ) evoke adverse and sometimes irreversible effects on the fetal/postnatal brain ( Mughal et al., 2018 ) but with a so far unknown effect on (SVZ-)NSCs.…”

Current Concepts of Neural Stem/Progenitor Cell Therapy for Chronic Spinal Cord Injury

“…We list the review articles on NSCs/NPCs treatment for chronic SCI in Table 4. Many therapeutic approaches have been reviewed in these articles in the attempt to treat chronic SCI, and many studies reported that cellular transplantation offered the greatest promise in reconstituting the architecture of the damaged spinal cord (McDonald et al, 1999;Curt, 2012;Jin et al, 2016;Yousefifard et al, 2016;Lane et al, 2017;Dalamagkas et al, 2018;Tsuji et al, 2019;Nagoshi et al, 2020;Platt et al, 2020;Vancamp et al, 2020;Suzuki and Sakai, 2021). Most of the ongoing clinical trials are targeting acute to subacute SCI; however, several are including the chronic phase as well (Table 4).…”

New Epidermal-Growth-Factor-Related Insights Into the Pathogenesis of Multiple Sclerosis: Is It Also Epistemology?

“…EGF is also a positive regulator of thyroid cell proliferation (35), and tri-iodothyronine plays a key role in the timing of OPC differentiation by stopping OPC proliferation and starting their terminal differentiation (36,37). Therefore, it is no accident that tri-iodothyronine has been successfully used to treat experimental allergic encephalomyelitis (EAE) (36), cuprizone-induced CNS demyelination, and MS (38,39).…”