Mouse digit tip regeneration is mediated by fate-restricted progenitor cells

Lehoczky, Jessica A.; Robert, Benoît; Tabin, Clifford J.

doi:10.1073/pnas.1118017108

Cited by 185 publications

(246 citation statements)

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“…4 G and H-H′′) and are likely originating from the resident Lgr6-expressing cells within the bone. (6). For example, in our hands, mice of the C57BL/6 inbred background, on which the Lgr6 allele is carried, are poor at digit tip regeneration whereas the outbred, CD-1(ICR) strain is much more robust in this respect.…”

Section: Lgr5 Expression Marks Mesenchymal Progenitors Local To Specimentioning

confidence: 84%

“…All alleles were maintained as heterozygotes or compound heterozygotes on the C57BL/6J background (JAX 000664), with the exception of the experimental outcross of Lgr6 EGFP-ires-creERT2 to CD-1(ICR) (022; Charles River Laboratories), where we performed an intercross of (Lgr6 EGFP-ires-creERT2 × CD-1(ICR))F1 animals. Expression and lineage analyses were performed by breeding genetic allele(s) to WT CD-1(ICR) females (022; Charles River Laboratories) to generate large litters for analysis and progeny with robust regeneration (6).…”

Section: Methodsmentioning

confidence: 99%

“…The digit tip regenerates via epimorphic regeneration, a process characterized by the intermediate formation of a blastema, a collection of morphologically undifferentiated mesenchymal cells derived from the underlying tissue. Previous work has shown that the digit tip blastema comprises a heterogeneous population of lineage-restricted progenitor cells (6,7). Digit tip regeneration is under the constraint of the nail organ, a keratinized ectodermal appendage unique to the digit tip.…”

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confidence: 99%

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Lgr6 marks nail stem cells and is required for digit tip regeneration

Lehoczky

Tabin

2015

Proc. Natl. Acad. Sci. U.S.A.

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The tips of the digits of some mammals, including human infants and mice, are capable of complete regeneration after injury. This process is reliant on the presence of the overlaying nail organ and is mediated by a proliferative blastema. Epithelial Wnt/β-catenin signaling has been shown to be necessary for mouse digit tip regeneration. Here, we report on Lgr5 and Lgr6 (leucine-rich repeat-containing G protein-coupled receptor 5 and 6), two important agonists of the Wnt pathway that are known to be markers of several epithelial stem cell populations. We find that Lgr5 is expressed in a dermal population of cells adjacent to the specialized epithelia surrounding the keratinized nail plate. Moreover, Lgr5-expressing cells contribute to this dermis, but not the blastema, during digit tip regeneration. In contrast, we find that Lgr6 is expressed within cells of the nail matrix portion of the nail epithelium, as well as in a subset of cells in the bone and eccrine sweat glands. Genetic lineage analysis reveals that Lgr6-expressing cells give rise to the nail during homeostatic growth, demonstrating that Lgr6 is a marker of nail stem cells. Moreover, Lgr6-expressing cells contribute to the blastema, suggesting a potential direct role for Lgr6-expressing cells during digit tip regeneration. This role is confirmed by analysis of Lgr6-deficient mice, which have both a nail and bone regeneration defect.

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Section: Lgr5 Expression Marks Mesenchymal Progenitors Local To Specimentioning

confidence: 84%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Lgr6 marks nail stem cells and is required for digit tip regeneration

Lehoczky

Tabin

2015

Proc. Natl. Acad. Sci. U.S.A.

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116

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“…Recent lineage-tracing studies have demonstrated that tissue-resident stem and progenitor cells that are fate-restricted in their developmental potential are responsible for appendage regeneration of fish, salamanders, and mice (13)(14)(15)(16). These cumulative data demonstrate that fate-restricted stem/progenitors as cells of origin, rather than dedifferentiation or transdifferentiation of terminally differentiated cells, represents an evolutionarily conserved cellular mechanism that explains the observed regrowth of the vertebrate appendages.…”

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confidence: 90%

Clonal analysis reveals nerve-dependent and independent roles on mammalian hind limb tissue maintenance and regeneration

Rinkevich

Montoro²,

Muhonen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The requirement and influence of the peripheral nervous system on tissue replacement in mammalian appendages remain largely undefined. To explore this question, we have performed genetic lineage tracing and clonal analysis of individual cells of mouse hind limb tissues devoid of nerve supply during regeneration of the digit tip, normal maintenance, and cutaneous wound healing. We show that cellular turnover, replacement, and cellular differentiation from presumed tissue stem/progenitor cells within hind limb tissues remain largely intact independent of nerve and nerve-derived factors. However, regenerated digit tips in the absence of nerves displayed patterning defects in bone and nail matrix. These nerve-dependent phenotypes mimic clinical observations of patients with nerve damage resulting from spinal cord injury and are of significant interest for translational medicine aimed at understanding the effects of nerves on etiologies of human injury.pattern formation | peripheral nerve | stem cell T he regrowth of vertebrate appendages has been considered a classic model system for interrogating the mechanisms and requirements for tissue/organ generation and regeneration across various phyla (1-5). Urodeles regenerate entire limbs by proliferation of fate-restricted stem and progenitor cells and form a blastema, the collection of cells at the interface of stump and wound epidermis, in a process mediated by nerve-derived factors (6-10). In Urodeles, surgical denervation before amputation results in the inhibition of blastema formation, and ultimately results in regeneration failure. Evidence from fish and amphibians suggests that nerve dependence may be a function of a threshold level of nerve factors with a direct correlation between nerve fibers and degree of regeneration (3,11,12) and supports the idea that nerve dependence may be an evolutionarily conserved requirement for the regeneration of vertebrate limb tissues.Mammalian limbs consist of multiple tissues that are derived from various embryonic origins and germ layers, including embryonic ectoderm, embryonic mesoderm, and embryonic neuralcrest. Recent lineage-tracing studies have demonstrated that tissue-resident stem and progenitor cells that are fate-restricted in their developmental potential are responsible for appendage regeneration of fish, salamanders, and mice (13-16). These cumulative data demonstrate that fate-restricted stem/progenitors as cells of origin, rather than dedifferentiation or transdifferentiation of terminally differentiated cells, represents an evolutionarily conserved cellular mechanism that explains the observed regrowth of the vertebrate appendages.Collectively, the commonalities of nerve dependence and stem/ progenitor fate restriction across vertebrate phyla further highlight the possibility that nerve dependence on appendage regrowth may take place within mammals, and possibly humans. In support of this, human clinical reports indicate that skin complications are manifested in response to spinal cord injury (SCI), suggesting a...

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“…At the other end of the spectrum, many birds and mammals regenerate poorly as adults. For instance, laboratory mice can regenerate their digit tips, but only providing the amputation occurs within the nail bed (Lehoczky et al, 2011) in a process that relies on resident stem cells (Rinkevich et al, 2011). Many salamanders on the other hand can regenerate their limbs, tails, eyes and even jaws (e.g.…”

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confidence: 99%

Amphioxus regeneration: evolutionary and biomedical implications

Somorjai

2017

Int. J. Dev. Biol.

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Regeneration is a variable trait in chordates, with some species capable of impressive abilities, and others of only wound healing with scarring. Regenerative capacity has been reported in the literature for 5 species from two cephalochordate genera, Branchiostoma and Asymmetron. Its cellular and molecular bases have been studied in some detail in only two species: tail regeneration in the European amphioxus B. lanceolatum; and oral cirrus regeneration in the Asian species B. japonicum. Gene expression analyses of germline formation and posterior elongation in cephalochordate embryos provide some insight into regulation of progenitor and stem cell function. When combined with functional studies of gene function, including overexpression and knockdown, these will open the door to amphioxus as a good model not only for understanding the evolution of regeneration, but also for biomedical purposes.

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Mouse digit tip regeneration is mediated by fate-restricted progenitor cells

Cited by 185 publications

References 35 publications

Lgr6 marks nail stem cells and is required for digit tip regeneration

Lgr6 marks nail stem cells and is required for digit tip regeneration

Clonal analysis reveals nerve-dependent and independent roles on mammalian hind limb tissue maintenance and regeneration

Amphioxus regeneration: evolutionary and biomedical implications

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