Germ-layer and lineage-restricted stem/progenitors regenerate the mouse digit tip

Rinkevich, Yuval; Lindau, Paul; Ueno, Hikaru; Longaker, Michael T.; Weissman, Irving L.

doi:10.1038/nature10346

Cited by 352 publications

(434 citation statements)

References 45 publications

(39 reference statements)

Supporting

Mentioning

409

Contrasting

Order By: Relevance

“…Thus, labeling is independent of a change in marker gene expression that could occur after denervation. Despite the chance of two adjacent cells being similarly colored, we and others (16,22,23) have found that lineage tracing over long periods of time uncovers a faithful cellular readout to that observed using tissue-specific or stem cellspecific reporters. Furthermore, as this assay can be used broadly to trace all cell types, it allows clonal analysis of even rare and asyet-unidentified tissue stem cells that may be activated on denervation and that would not be uncovered using existing stem cell reporters.…”

Section: Resultsmentioning

confidence: 65%

“…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.…”

mentioning

confidence: 94%

See 1 more Smart Citation

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.

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Section: Resultsmentioning

confidence: 65%

mentioning

confidence: 94%

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.

Self Cite

View full text Add to dashboard Cite

show abstract

“…This is a story of a very long trip from tolerance to T and B cell maturation to stem cells. [I have discussed HSCs, but we have also isolated and transplanted human central nervous system stem cells in clinical trials (254); we have isolated a number of other tissue and cancer stem cells (124,127,193,(255)(256)(257)(258)(259)(260)(261)(262)(263)(264)(265)(266), and many are in progress to investigational therapies.] It is a story with some cautions about human motivations, commerce, and clinical translation.…”

Section: Cancer Stem Cells and The Therapeutics That Come From Them: mentioning

confidence: 99%

How One Thing Led to Another

Weissman

2016

Annu. Rev. Immunol.

View full text Add to dashboard Cite

I started research in high school, experimenting on immunological tolerance to transplantation antigens. This led to studies of the thymus as the site of maturation of T cells, which led to the discovery, isolation, and clinical transplantation of purified hematopoietic stem cells (HSCs). The induction of immune tolerance with HSCs has led to isolation of other tissue-specific stem cells for regenerative medicine. Our studies of circulating competing germline stem cells in colonial protochordates led us to document competing HSCs. In human acute myelogenous leukemia we showed that all preleukemic mutations occur in HSCs, and determined their order; the final mutations occur in a multipotent progenitor derived from the preleukemic HSC clone. With these, we discovered that CD47 is an upregulated gene in all human cancers and is a “don't eat me” signal; blocking it with antibodies leads to cancer cell phagocytosis. CD47 is the first known gene common to all cancers and is a target for cancer immunotherapy.

show abstract

“…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.…”

mentioning

confidence: 99%

Amphioxus regeneration: evolutionary and biomedical implications

Somorjai

2017

Int. J. Dev. Biol.

View full text Add to dashboard Cite

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.

show abstract

Germ-layer and lineage-restricted stem/progenitors regenerate the mouse digit tip

Cited by 352 publications

References 45 publications

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

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

How One Thing Led to Another

Amphioxus regeneration: evolutionary and biomedical implications

Contact Info

Product

Resources

About