The regenerative capacity of the peripheral nervous system declines with age. Why this occurs, however, is unknown. We demonstrate that 24-month-old mice exhibit an impairment of functional recovery ...after nerve injury compared to 2-month-old animals. We find no difference in the intrinsic growth capacity between aged and young sensory neurons in vitro or in their ability to activate growth-associated transcriptional programs after injury. Instead, using age-mismatched nerve transplants in vivo, we show that the extent of functional recovery depends on the age of the nerve graft, and not the age of the host. Molecular interrogation of the sciatic nerve reveals that aged Schwann cells (SCs) fail to rapidly activate a transcriptional repair program after injury. Functionally, aged SCs exhibit impaired dedifferentiation, myelin clearance, and macrophage recruitment. These results suggest that the age-associated decline in axonal regeneration results from diminished Schwann cell plasticity, leading to slower myelin clearance.
•Aged mice exhibit diminished functional recovery after nerve injury•Aged neuronal regeneration responses remain robust•Transplantation of young nerve grafts into old hosts rejuvenates regeneration•Aged Schwann cells exhibit diminished capacity for myelin clearance
Why aging results in diminished peripheral nerve regeneration remains a clinical problem and a biological puzzle. In this issue, Painter et al. demonstrate that Schwann cell injury responses decline with aging, providing key insight into the aging peripheral nervous system.
Chronic neuropathic pain is a major morbidity of neural injury, yet its mechanisms are incompletely understood. Hypersensitivity to previously non-noxious stimuli (allodynia) is a common symptom. ...Here, we demonstrate that the onset of cold hypersensitivity precedes tactile allodynia in a model of partial nerve injury, and this temporal divergence was associated with major differences in global gene expression in innervating dorsal root ganglia. Transcripts whose expression change correlates with the onset of cold allodynia were nociceptor related, whereas those correlating with tactile hypersensitivity were immune cell centric. Ablation of TrpV1 lineage nociceptors resulted in mice that did not acquire cold allodynia but developed normal tactile hypersensitivity, whereas depletion of macrophages or T cells reduced neuropathic tactile allodynia but not cold hypersensitivity. We conclude that neuropathic pain incorporates reactive processes of sensory neurons and immune cells, each leading to distinct forms of hypersensitivity, potentially allowing drug development targeted to each pain type.
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•Peripheral processes leading to neuropathic cold and tactile allodynia differ•TrpV1-lineage neurons participate in cold, but not tactile, allodynia•Immune system activation contributes to tactile allodynia but minimally to cold allodynia
Cobos et al. correlated gene expression with behavior after nerve injury and found that two distinct processes contribute to neuropathic pain: one that occurs in neurons, leading to cold allodynia, and another that includes immune cells and neurons, leading to tactile allodynia.
Axon regeneration in the CNS requires reactivating injured neurons’ intrinsic growth state and enabling growth in an inhibitory environment. Using an inbred mouse neuronal phenotypic screen, we find ...that CAST/Ei mouse adult dorsal root ganglion neurons extend axons more on CNS myelin than the other eight strains tested, especially when pre-injured. Injury-primed CAST/Ei neurons also regenerate markedly in the spinal cord and optic nerve more than those from C57BL/6 mice and show greater sprouting following ischemic stroke. Heritability estimates indicate that extended growth in CAST/Ei neurons on myelin is genetically determined, and two whole-genome expression screens yield the Activin transcript Inhba as most correlated with this ability. Inhibition of Activin signaling in CAST/Ei mice diminishes their CNS regenerative capacity, whereas its activation in C57BL/6 animals boosts regeneration. This screen demonstrates that mammalian CNS regeneration can occur and reveals a molecular pathway that contributes to this ability.
•Long-distance CNS axon regeneration in mammals is possible without genetic manipulation•Pre-injured CAST/Ei sensory neurons grow on diverse growth-inhibitory substrates•CNS regeneration occurs in CAST/Ei mice through Activin signaling•Enhancing Activin signaling confers CNS regenerative capacity in C57/B6 mice
Omura et al. screened for neuronal growth on myelin and find CAST/Ei inbred mice are uniquely able to regenerate axons in the injured CNS through Activin signaling. Enhancing Activin signaling confers a CNS-regenerative capacity in normally non-regenerative mouse strains.
The Immunological Genome Project combines immunology and computational biology laboratories in an effort to establish a complete 'road map' of gene-expression and regulatory networks in all immune ...cells.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Peripheral nerve regeneration after injury requires a broad program of transcriptional changes. We investigated the basis for the enhanced nerve regenerative capacity of the CAST/Ei mouse strain ...relative to C57BL/6 mice. RNA sequencing of dorsal root ganglia (DRG) showed a CAST/Ei-specific upregulation of Ascl1 after injury. Ascl1 overexpression in DRG neurons of C57BL/6 mice enhanced their neurite outgrowth. Ascl1 is regulated by miR-7048-3p, which is downregulated in CAST/Ei mice. Inhibition of miR-7048-3p enhances neurite outgrowth. Following injury, CAST/Ei neurons largely retained their mature neuronal profile as determined by single-cell RNA- seq, whereas the C57BL/6 neurons acquired an immature profile. These findings suggest that one facet of the enhanced regenerative phenotype is preservation of neuronal identity in response to injury.
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•Superior regeneration of CAST/Ei mice is associated with increased Ascl1 expression•Increased Ascl expression promotes nerve regeneration•CAST/Ei mice retain more mature neurons after DRG injury than do C57BL/6 mice
Lisi et al. find that increased Ascl1 expression is associated with the superior regenerative capacity of CAST/Ei mice. Single-cell RNA-seq demonstrated that CAST/Ei mice retained more mature neurons after injury than did C57BL/6 mice, thereby suggesting that genetic drivers of the enhanced regenerative phenotype include mechanisms to preserve neuronal identity after injury.
T and B lymphocytes are developmentally and functionally related cells of the immune system, representing the two major branches of adaptive immunity. Although originating from a common precursor, ...they play very different roles: T cells contribute to and drive cell-mediated immunity, whereas B cells secrete Abs. Because of their functional importance and well-characterized differentiation pathways, T and B lymphocytes are ideal cell types with which to understand how functional differences are encoded at the transcriptional level. Although there has been a great deal of interest in defining regulatory factors that distinguish T and B cells, a truly genomewide view of the transcriptional differences between these two cells types has not yet been taken. To obtain a more global perspective of the transcriptional differences underlying T and B cells, we exploited the statistical power of combinatorial profiling on different microarray platforms, and the breadth of the Immunological Genome Project gene expression database, to generate robust differential signatures. We find that differential expression in T and B cells is pervasive, with the majority of transcripts showing statistically significant differences. These distinguishing characteristics are acquired gradually, through all stages of B and T differentiation. In contrast, very few T versus B signature genes are uniquely expressed in these lineages, but are shared throughout immune cells.
Axon regeneration in the central nervous system (CNS) requires reactivating injured neurons’ intrinsic growth state and enabling growth in an inhibitory environment. Using an inbred mouse neuronal ...phenotypic screen, we find that CAST/Ei mouse adult dorsal root ganglion neurons extend axons more on CNS myelin than the other eight strains tested, especially when pre-injured. Injury-primed CAST/Ei neurons also regenerate markedly in the spinal cord and optic nerve more than those from C57BL/6 mice and show greater spouting following ischemic stroke. Heritability estimates indicate that extended growth in CAST/Ei neurons on myelin is genetically determined, and two whole-genome expression screens yield the Activin transcript
Inhba
as most correlated with this ability. Inhibition of Activin signaling in CAST/Ei mice diminishes their CNS regenerative capacity whereas its activation in C57BL/6 animals boosts regeneration. This screen demonstrates that mammalian CNS regeneration can occur and reveals a molecular pathway that contributes to this ability.
T and B lymphocytes are developmentally and functionally related cells of the immune system, representing the two major branches of adaptive immunity. Although originating from a common precursor, ...they play very different roles: T cells contribute to and drive cell-mediated immunity, while B cells secrete antibodies. Because of their functional importance and well-characterized differentiation pathways, T and B lymphocytes are ideal cell-types with which to understand how functional differences are encoded at the transcriptional level. Although there has been a great deal of interest in defining regulatory factors that distinguish T and B cells, a truly genome-wide view of the transcriptional differences between these two cells types has not yet been taken. To obtain a more global perspective of the transcriptional differences underlying T and B cells, we exploited the statistical power of combinatorial profiling on different microarray platforms, and the breadth of the Immunological Genome Project (ImmGen) gene-expression database, to generate robust differential signatures. We find that differential expression in T and B cells is pervasive, the majority of transcripts showing statistically significant differences. These distinguishing characteristics are acquired gradually, though all stages of B and T differentiation. On the other hand, very few T vs. B signature genes are uniquely expressed in these lineages, but are shared throughout immune cells.
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