Star power: harnessing the reactive astrocyte response to promote remyelination in multiple sclerosis

Astrocytes are indispensable for central nervous system development and homeostasis.In response to injury and disease,astrocytes are integral to the immunological-and the,albeit limited,repair response.In this review,we will examine some of the functions reactive astrocytes play in the context of multiple sclerosis and related animal models.We will consider the heterogeneity or plasticity of astrocytes and the mechanisms by which they promote or mitigate demyelination.Finally,we will discuss a set of biomedical strategies that can stimulate astrocytes in their promyelinating response.

Multiple sclerosis drug repurposing for neuroregeneration

Multiple sclerosis(MS)is an autoimmune disorder of the central nervous system(CNS)and is primarily characterized by immune cell infiltration leading to relapses followed by remission phases and a disease course turning progressive over time with neurodegenerative processes taking over(Amin and Hersh,2023).Of note,beyond relapse-associated worsening early in disease progression independent of relapse activity may arise independently of relapse activity and can occur in all phenotypes.Autoimmune-mediated damage of myelin sheaths and the subsequent loss of mature oligodendrocytes are resulting in impaired axonal integrity,neurodegeneration and accounts for irreversible neuronal damage(Kuhlmann et al.,2023).The current landscape of available disease-modifying therapies comprises mainly immunomodulatory drugs that effectively diminish relapses and slow down progression at the onset form of the disease,namely relapsing MS(RMS).In this regard,a number of drugs have been approved as disease-modifying therapies for MS by US Food and Drug Administration and European Medicines Agencies(Box 1).

Human endogenous retrovirus type-W and multiple sclerosis–related smoldering neuroinflammation

Introduction to human endogenous retrovirus type-W(HERV-W): Genomic inheritance from the past includes retroviral sequences that have been stably incorporated into our genomes and account for up to 8% of human DNA.

Heterogeneous populations of neural stem cells contribute to myelin repair

As ingenious as nature＇s invention of myelin sheaths within the mammalian nervous system is, as fatal can be damage to this specialized lipid structure. Long-term loss of electrical insulation and of further supportive functions myelin provides to axons, as seen in demyelinating diseases such as multiple sclerosis （MS）, leads to neurodegeneration and results in progressive disabilities. Multiple lines of evidence have demon-strated the increasing inability of oligodendrocyte precursor cells （OPCs） to replace lost oligodendrocytes （OLs） in order to restore lost myelin. Much research has been dedicated to reveal potential reasons for this regeneration deficit but despite promising approaches no remyelination-promoting drugs have successfully been developed yet. In addition to OPCs neural stem cells of the adult central nervous system also hold a high potential to generate myelinating OLs. There are at least two neural stem cell niches in the brain, the subventricular zone lining the lateral ventricles and the subgranular zone of the dentate gyrus, and an additional source of neural stem cells has been located in the central canal of the spinal cord. While a substantial body of literature has described their neurogenic capacity, still little is known about the oligodendrogenic potential of these cells, even if some animal studies have provided proof of their contribution to remyelination. In this review, we summarize and discuss these studies, taking into account the different niches, the heterogeneity within and between stem cell niches and present current strategies of how to promote stem cell-mediated myelin repair.

Novel approaches for the development of peripheral nerve regenerative therapies

Schwann cells are the myelinating glial cells of the peripheral nervous system（PNS）.By establishing lipid-rich myelin sheaths around large-caliber axons,they ensure that electrical signal transmission is accelerated-a process referred to as saltatory signal propagation.Apart from this prominent physiological function,these cells also exert important pathophysiological roles in PNS injuries or dis- eases. In contrast to the central nervous system （CNS）, the adult PNS retains a remarkably high degree of intrinsic re- generation. As a consequence, transected axons and dam- aged myelin sheaths can be repaired and nerve functional- ity can be restored. This spontaneous regenerative capacity depends on （inter） actions of macrophages, neurons, and Schwann cells.

Functional in vivo assessment of stem cell-secreted pro-oligodendroglial factors

The role of adult neural stem cells(NSCs)in demyelinating diseases of the central nervous system(CNS):Multipotent NSCs hold great potential for cell replacement in diseases and upon injury of the CNS.Originating from radial glial cells during nervous system development,adult NSCs are localized in the subgranular zone of the hippocampus and the subventricular zone(SVZ)of the lateral brain ventricles,the main neurogenic zones of the adult brain.Hippocampal precursor cells(type 1 cells)exhibiting properties of radial glial cells give rise to granule neurons through distinct intermediate precursor cells,and integrate into the hippocampal circuitry[reviewed by Kempermann et al.(2015)].Likewise,under physiological conditions,neuron generation by mouse SVZ-derived NSCs(also known as type B cells)is the predominant cell fate,which thereby results in large numbers of transient amplifying precursor cells(also known as type C cells)which in turn differentiate into neuroblasts(type A cells).These cells migrate along the rostral migratory stream into the olfactory bulb where they undergo maturation into local interneurons.The structure of the rodent SVZ differs from that of the human SVZ since the proliferative capacity is reduced,and migration of neuroblasts is a rare event in adult humans[reviewed by Lim and Alvarez-Buylla(2016)].

Human endogenous retroviruses: ammunition for myeloid cells in neurodegenerative diseases?

Activation of myeloid cells by human endogenous retroviral entities:While the exact causes of neurological diseases such as multiple sclerosis(MS)or amyotrophic lateral sclerosis(ALS)are still elusive,there is evidence of a new category of pathogenic elements called human endogenous retroviruses(HERVs)which seem to contribute to their evolution and progression by exerting inflammatory and degenerative effects(Kury et al.,2018).HERVs are ancient retroviral elements which account for up to 8%of the human genome and it is known that environmental factors can trigger their(re-)expression(Kury et al.,2018).The resulting production of viral particles and/or proteins,especially from members of the HERV-W and HERV-K family,is strongly correlated with the onset and progression of neurological diseases,such as MS and ALS(Kury et al.,2018).