Mesenchymal Precursor Cells in Adult Nerves Contribute to Mammalian Tissue Repair and Regeneration

Carr, Matthew; Toma, Jeremy S.; Johnston, Adam; Steadman, Patrick E.; Yuzwa, Scott A.; Mahmud, Neemat; Frankland, Paul W.; Kaplan, David R.; Miller, Freda D.

doi:10.1016/j.stem.2018.10.024

Cited by 174 publications

(275 citation statements)

References 36 publications

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“…To begin to understand the biological significance of the seven discrete 11dpa fibroblast populations, we investigated the cluster marker genes that specifically mark these populations (Supplemental Table 1A). While all fibroblast clusters have gene expression in common, such as Prrx1, Msx1, and Pdgfra (Carr et al, 2018; Lehoczky et al, 2011; Rinkevich et al, 2011), these broad fibroblast markers ultimately mask the underlying heterogeneity of fibroblasts in the blastema. In line with the dendrogram and correlation matrix, clusters 0, 1, and 2 show common expression of many genes like Ndnf , Matn4 , and Mest (Supplemental Figure 1C).…”

Section: Resultsmentioning

confidence: 99%

Cellular heterogeneity and lineage restriction during mouse digit tip regeneration at single cell resolution

Johnson

Masias

Lehoczky

2019

Preprint

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14Innate regeneration following digit tip amputation is one of the few examples of epimorphic 15 regeneration in mammals. Digit tip regeneration is mediated by the blastema, the same structure 16 invoked during limb regeneration in some lower vertebrates. By genetic lineage analyses in 17 mice, the digit tip blastema has been defined as a population of heterogeneous, lineage restricted 18 progenitor cells. These previous studies, however, do not comprehensively evaluate blastema 19 heterogeneity or address lineage restriction of closely related cell types. In this report we present 20 single cell RNA sequencing of over 38,000 cells from mouse digit tip blastemas and 21 unamputated control digit tips and generate an atlas of the cell types participating in digit tip 22 regeneration. We define the differentiation trajectories of vascular, monocytic, and fibroblastic 23 lineages over regeneration, and while our data confirm broad lineage restriction of progenitors, 24 our analysis reveals an early blastema fibroblast population expressing a novel regeneration-25

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Section: Resultsmentioning

confidence: 99%

Cellular heterogeneity and lineage restriction during mouse digit tip regeneration at single cell resolution

Johnson

Masias

Lehoczky

2019

Preprint

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“…Since typically, 50% of nuclei express c-jun, a marker for Schwann cells response to injury, two days after injury in the nerve (Blom et al, 2014), the GFP positive nuclei we observed, may represent a very small subset of Schwann cells responding to injury. To further confirm the specificity of the BLBPCreER reporter following nerve injury, we re-analyzed a single cell data set from injured nerve (9 days post injury) (Carr et al, 2019). We found that less than 5% of cells in the Schwann cell cluster expressed Fabp7 ( Figure S2D).…”

Section: Sgc Are Molecularly Distinct From Schwann Cells In Drgmentioning

confidence: 90%

Satellite glial cells promote regenerative growth in sensory neurons

Avraham

Deng

Jones

et al. 2019

Preprint

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Peripheral sensory neurons switch to a regenerative state after nerve injury to enable axon regeneration and functional recovery. Whether satellite glial cells (SGC), which completely surround the neuronal soma, contribute to the regenerative responses remains unexplored. Here we defined the transcriptional profile of SGC and identified Fabp7/BLBP as a novel marker of SGC. We report that nerve injury changes gene expression in SGC, which is mostly related to lipid metabolism, specifically fatty acid synthesis and PPARa signaling. Conditional deletion of Fatty acid synthase (Fasn), the committed enzyme in de novo fatty acid synthesis in SGC impairs axon regeneration. Treatment with the PPARa agonist fenofibrate rescues axon regeneration in mice lacking Fasn in SGC. This results indicates that PPARa functions downstream of fatty acid synthesis in SGC to promote axon regeneration. These results identify fatty acid synthesis in SGC as a fundamental novel mechanism mediating axon regeneration in adult peripheral nerves.

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“…In addition to SCs, the endoneurium also contains tissue‐resident macrophages, endothelial cells and associated pericytes (Jessen et al, ). Furthermore, a new cell type was characterised recently that, while previously described as endoneurial fibroblasts (Joseph et al, ), is of unknown function in the homeostatic nerve, expresses markers of both pericytes and mesenchymal cells and makes contacts with different cell types within the endoneurium leading to them being re‐named as tactocytes (Carr et al, ; Stierli et al, ).…”

Section: Peripheral Nerve Homeostasismentioning

confidence: 99%

Schwann cell plasticity‐roles in tissue homeostasis, regeneration, and disease

Stierli

Imperatore

Lloyd

2019

Glia

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How tissues are maintained over a lifetime and repaired following injury are fundamental questions in biology with a disruption to these processes underlying pathologies such as cancer and degenerative disorders. It is becoming increasingly clear that each tissue has a distinct mechanism to maintain homeostasis and respond to injury utilizing different types of stem/progenitor cell populations depending on the insult and/or with a contribution from more differentiated cells that are able to dedifferentiate to aid tissue regeneration. Peripheral nerves are highly quiescent yet show remarkable regenerative capabilities. Remarkably, there is no evidence for a classical stem cell population, rather all cell‐types within the nerve are able to proliferate to produce new nerve tissue. Co‐ordinating the regeneration of this tissue are Schwann cells (SCs), the main glial cells of the peripheral nervous system. SCs exist in architecturally stable structures that can persist for the lifetime of an animal, however, they are not postmitotic, in that following injury they are reprogrammed at high efficiency to a progenitor‐like state, with these cells acting to orchestrate the nerve regeneration process. During nerve regeneration, SCs show little plasticity, maintaining their identity in the repaired tissue. However, once free of the nerve environment they appear to exhibit increased plasticity with reported roles in the repair of other tissues. In this review, we will discuss the mechanisms underlying the homeostasis and regeneration of peripheral nerves and how reprogrammed progenitor‐like SCs have broader roles in the repair of other tissues with implications for pathologies such as cancer.

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Mesenchymal Precursor Cells in Adult Nerves Contribute to Mammalian Tissue Repair and Regeneration

Cited by 174 publications

References 36 publications

Cellular heterogeneity and lineage restriction during mouse digit tip regeneration at single cell resolution

Cellular heterogeneity and lineage restriction during mouse digit tip regeneration at single cell resolution

Satellite glial cells promote regenerative growth in sensory neurons

Schwann cell plasticity‐roles in tissue homeostasis, regeneration, and disease

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