Axonal regrowth is impaired during digit tip regeneration in mice

Dolan, Connor P.; Yan, Mingquan; Zimmel, Katherine; Yang, Tae-Jung; Leininger, Eric; Dawson, Lindsay A.; Muneoka, Ken

doi:10.1016/j.ydbio.2018.11.010

Cited by 16 publications

(28 citation statements)

References 56 publications

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“…Notably, the myelinating Schwann cells remain significantly reduced through all of our assayed stages and do not reinstate pre-amputation levels by 17dpa. This observation is in line with previous work, which showed that Schwann cells are present in the blastema but are qualitatively less abundant than in the quiescent digit tip, and only non-myelinating Schwann cells appear to recover to pre-amputation levels by 4 weeks post amputation (Dolan et al, 2019; Johnston et al, 2016). The reduction in population size of non-myelinating Schwann cells persists through 14dpa and begins to recover to pre-amputation levels by 17dpa.…”

Section: Resultssupporting

confidence: 92%

“…Previous studies demonstrate that innervation and neural associated cell types such as Schwann cell precursors are necessary for digit tip regeneration (Carr et al, 2018; Dolan et al, 2019; Johnston et al, 2016; Mohammad and Neufeld, 2000; Takeo et al, 2013). Both sensory and sympathetic axons innervate the connective tissue of the unamputated digit tip, and they are accompanied by both myelinating and non-myelinating Schwann cells (Dolan et al, 2019). In the unamputated digit tip, we find that myelinating and non-myelinating Schwann cells make up 0.40% and 1.9% of the captured cells, respectively.…”

Section: Resultsmentioning

confidence: 99%

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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: Resultssupporting

confidence: 92%

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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“…The avascularity of the blastema corresponds with regional shifts in hypoxia during the regeneration response (Sammarco et al, 2014). The digit blastema is also aneural and less than 20% of the axons transected by amputation successfully innervate the regenerated digit tip (Dolan et al, 2019).…”

Section: Quick Review: Epimorphic Regeneration Of the Mouse Digit Tipmentioning

confidence: 99%

“…In digit tip regeneration, limb denervation inhibits the production of a number of factors (FGF2, PDGF, and Oncostatin) that stimulate proliferation of blastema cells; FGF2 is produced by nail epithelial cells (Takeo et al, 2013) while PDGF and Oncostatin are produced by Schwann cells (Johnston et al, 2016). The role that axonal regrowth plays in nerve‐dependent regeneration in mammals is questioned by findings that mammalian peripheral nerves are known to regenerate poorly (Stankovic, Johansson, & Hildebrand, 1996) and that the regenerated digit tip is not the exception to this rule (Dolan et al, 2019). Analysis of digit tip regeneration indicates that axonal regrowth is severely impaired yet repeat amputation of the regenerated digit tip is successful (Dolan et al, 2019).…”

Section: Phylogenetic Changes In Digit Regenerationmentioning

confidence: 99%

“…The role that axonal regrowth plays in nerve‐dependent regeneration in mammals is questioned by findings that mammalian peripheral nerves are known to regenerate poorly (Stankovic, Johansson, & Hildebrand, 1996) and that the regenerated digit tip is not the exception to this rule (Dolan et al, 2019). Analysis of digit tip regeneration indicates that axonal regrowth is severely impaired yet repeat amputation of the regenerated digit tip is successful (Dolan et al, 2019). Detailed analyses of the regenerating digit blastema show that the blastema is lacking in regenerating axons as well as Schwann cells, and this suggests that nerve‐dependent blastema cell proliferation is not directly mediated by regenerating axons.…”

Section: Phylogenetic Changes In Digit Regenerationmentioning

confidence: 99%

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Evolution of epimorphosis in mammals

Muneoka

Dawson

2020

J Exp Zool Pt B

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Mammalian epimorphic regeneration is rare and digit tip regeneration in mice is the best‐studied model for a multi‐tissue regenerative event that involves blastema formation. Digit tip regeneration parallels human fingertip regeneration, thus understanding the details of this response can provide insight into developing strategies to expand the potential of human regeneration. Following amputation, the digit stump undergoes a strong histolytic response involving osteoclast‐mediated bone degradation that is spatially and temporally linked to the expansion of blastema osteoprogenitor cells. Blastemal differentiation occurs via direct intramembranous ossification. Although robust, digit regeneration is imperfect: The amputated cortical bone is replaced with woven bone and there is excessive bone regeneration restricted to the dorsal–ventral axis. Ontogenetic and phylogenetic analysis of digit regeneration in amphibians and mammals raise the possibility that mammalian blastema is a product of convergent evolution and we hypothesize that digit tip regeneration evolved from a nonregenerative precondition. A model is proposed in which the mammalian blastema evolved in part from an adaptation of two bone repair strategies (the bone remodeling cycle and fracture healing) both of which are conserved across tetrapod vertebrates. The view that epimorphic regeneration evolved in mammals from a nonregenerative precondition is supported by recent studies demonstrating that complex regenerative responses can be induced from a number of different nonregenerative amputation wounds by specific modification of the healing response.

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Crosstalk between Bone and Nerves within Bone

et al. 2021

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For the past two decades, the function of intrabony nerves on bone has been a subject of intense research, while the function of bone on intrabony nerves is still hidden in the corner. In the present review, the possible crosstalk between bone and intrabony peripheral nerves will be comprehensively analyzed. Peripheral nerves participate in bone development and repair via a host of signals generated through the secretion of neurotransmitters, neuropeptides, axon guidance factors and neurotrophins, with additional contribution from nerve‐resident cells. In return, bone contributes to this microenvironmental rendezvous by housing the nerves within its internal milieu to provide mechanical support and a protective shelf. A large ensemble of chemical, mechanical, and electrical cues works in harmony with bone marrow stromal cells in the regulation of intrabony nerves. The crosstalk between bone and nerves is not limited to the physiological state, but also involved in various bone diseases including osteoporosis, osteoarthritis, heterotopic ossification, psychological stress‐related bone abnormalities, and bone related tumors. This crosstalk may be harnessed in the design of tissue engineering scaffolds for repair of bone defects or be targeted for treatment of diseases related to bone and peripheral nerves.

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Axonal regrowth is impaired during digit tip regeneration in mice

Cited by 16 publications

References 56 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

Evolution of epimorphosis in mammals

Crosstalk between Bone and Nerves within Bone

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