Toll-like receptor 4 modulation influences human neural stem cell proliferation and differentiation

Abstract

Toll-like receptor 4 (TLR4) activation is pivotal to innate immunity and has been shown to regulate proliferation and differentiation of human neural stem cells (hNSCs) in vivo. Here we study the role of TLR4 in regulating hNSC derived from the human telencephalic-diencephalic area of the fetal brain and cultured in vitro as neurospheres in compliance with Good Manifacture Procedures (GMP) guidelines. Similar batches have been used in recent clinical trials in ALS patients. We found that TLR2 and 4 are expressed in hNSCs as well as CD14 and MD-2 co-receptors, and TLR4 expression is downregulated upon differentiation. Activation of TLR4 signaling by lipopolysaccharide (LPS) has a positive effect on proliferation and/or survival while the inverse is observed with TLR4 inhibition by a synthetic antagonist. TLR4 activation promotes neuronal and oligodendrocyte differentiation and/or survival while TLR4 inhibition leads to increased apoptosis. Consistently, endogenous expression of TLR4 is retained by hNSC surviving after transplantation in ALS rats or immunocompromised mice, thus irrespectively of the neuroinflammatory environment. The characterization of downstream signaling of TLR4 in hNSCs has suggested some activation of the inflammasome pathway. This study suggests TLR4 signaling as essential for hNSC self-renewal and as a novel target for the study of neurogenetic mechanisms.

The Absence of Toll-Like Receptor 4 Mildly Affects the Structure and Function in the Adult Mouse Retina

“…Mammalian TLRs have relevant roles in embryogenesis, development of neurons and neural circuits, learning and memory, with regulatory roles on the processes of proliferation, differentiation, outgrowth, plasticity and neuron survival (Rolls et al, 2007; Shechter et al, 2008; Hanke and Kielian, 2011; Okun et al, 2011; Barak et al, 2014; Grasselli et al, 2018). Thus, it is expected that TLRs contribute to the development and maintenance of retinal structure and function.…”

“…It is now evident that, far from their primary well-known function as mediators of the immune response, TLRs play additional relevant roles in the progression of different pathological conditions, such as non-infectious neuronal injuries and neurodegenerative disorders (Carty and Bowie, 2011; Hanke and Kielian, 2011; Okun et al, 2011; Feldman et al, 2015). Interestingly, recent findings show that TLRs also appear to be involved in many physiological cellular processes, such as the development of neuronal circuits during embryogenesis, progenitor cell proliferation and differentiation, CNS plasticity throughout the entire life or drug-reward behavior (Rolls et al, 2007; Shechter et al, 2008; Okun et al, 2011; Barak et al, 2014; Kashima and Grueter, 2017; Grasselli et al, 2018). So far, numerous endogenous TLR ligands have been identified that could play a role in the regulation of CNS physiological processes and in the development and progression of neurodegenerative disorders (Trotta et al, 2014).…”

Diverse Roles for Hyaluronan and Hyaluronan Receptors in the Developing and Adult Nervous System

“…TLR4 expression was observed on neural progenitors in the retina, and the activation of TLR4 decreased cell proliferation and induced the differentiation of progenitors into neurons [ 160 ]. Human NSCs express both TLR2 and TLR4, which decreased upon differentiation [ 161 ]. TLR4 inhibition decreased human NSC proliferation, while its activation increased differentiation rates [ 161 ].…”

“…Human NSCs express both TLR2 and TLR4, which decreased upon differentiation [ 161 ]. TLR4 inhibition decreased human NSC proliferation, while its activation increased differentiation rates [ 161 ].…”

Effect of alternan versus chitosan on the biological properties of human mesenchymal stem cells

“…TLR signaling has been shown to play a role in regulating differentiation of several cell types, including human neural stem cells, 30 and immunity-related cells like T-cells, B-cells, 31,32 and macrophages. 33 In MSCs, Pevsner-Fischer and colleagues showed that TLRs and their ligands can serve as a regulator of MSC proliferation and differentiation.…”