Limb Regeneration: Induction in the Newborn Opossum

Mizell, Merle

doi:10.1126/science.161.3838.283

Cited by 60 publications

(19 citation statements)

References 16 publications

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“…The biological significance of the 1␣,25(OH) 2 D 3 -induced NGF expression by osteoblastic cells has not yet been clarified. Regeneration after limb amputation can be successfully induced by transplanting nervous tissue to the lesioned limb (214,215), and symphatectomy may result in the loss of a trophic influence important in the regulation of osteogenesis (216). More recently, it was shown that topical application of NGF improves fracture healing in rats (217).…”

Section: Growth Factors In 1␣mentioning

confidence: 98%

Modulation of Growth Factor/Cytokine Synthesis and Signaling by 1α,25-Dihydroxyvitamin D3: Implications in Cell Growth and Differentiation

2002

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Distinct from its classic functions in the regulation of calcium and phosphorus metabolism as a systemic hormone, 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] is involved in the local control and regulation of cellular growth and differentiation in various tissues, including epidermis (keratinocytes) and bone (osteoblasts and osteoclasts). In this review, the impact of 1alpha,25(OH)(2)D(3) on growth factor/cytokine synthesis and signaling is discussed, particularly as it pertains to bone cells and keratinocytes. 1alpha,25(OH)(2)D(3) not only regulates growth factor/cytokine synthesis but may also alter growth factor signaling. Recently discovered examples for such interactions are the interactions between the vitamin D receptor and the mothers against decapentaplegic-related proteins that function downstream of TGFbeta receptors. Inhibitory effects of 1alpha,25(OH)(2)D(3) on keratinocytes through TGFbeta activation and IL-1alpha, IL-6, and IL-8 suppression may provide a rationale for its beneficial effects in the treatment of hyperproliferative skin disorders, whereas stimulatory effects through the epidermal growth factor-related family members and platelet-derived growth factor may be operative in its beneficial effects in skin atrophy and wound healing. Modulation of cytokines and growth factors by 1alpha,25(OH)(2)D(3) during bone remodeling plays an important role in the coupling of osteoblastic bone formation with osteoclastic resorption to maintain bone mass.

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Section: Growth Factors In 1␣mentioning

confidence: 98%

Modulation of Growth Factor/Cytokine Synthesis and Signaling by 1α,25-Dihydroxyvitamin D3: Implications in Cell Growth and Differentiation

2002

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“…Following the lead of Marcus Singer's studies on the neurotrophic influence in amphibian limb regeneration (Singer, 1952), Mizell reported on induced regeneration of amputated newborn opossum hind limbs by implantation of neural tissues (Mizell, 1968). However, in an effort to replicate these studies, Fleming and Tassava reported that anatomical variability in the timing of skeletal outgrowth of the opossum hindlimb, and not neural tissue grafts, could account for the partial regenerative response reported by Mizell (Fleming and Tassava, 1981;Mizell, 1968). The developing mammalian limb bud possesses an endogenous ability to undergo a partial regenerative response in vitro and in vivo, indicating that regenerative ability is enhanced during development (Chan et al, 1991;Deuchar, 1976;Wanek et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

BMP signaling induces digit regeneration in neonatal mice

et al. 2010

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SUMMARYThe regenerating digit tip of mice is a novel epimorphic response in mammals that is similar to fingertip regeneration in humans. Both display restricted regenerative capabilities that are amputation-level dependent. Using this endogenous regeneration model in neonatal mice, we have found that noggin treatment inhibits regeneration, thus suggesting a bone morphogenetic protein (BMP) requirement. Using non-regenerating amputation wounds, we show that BMP7 or BMP2 can induce a regenerative response. BMP-induced regeneration involves the formation of a mammalian digit blastema. Unlike the endogenous regeneration response that involves redifferentiation by direct ossification (evolved regeneration), the BMP-induced response involves endochondral ossification (redevelopment). Our evidence suggests that BMP treatment triggers a reprogramming event that re-initiates digit tip development at the amputation wound. These studies demonstrate for the first time that the postnatal mammalian digit has latent regenerative capabilities that can be induced by growth factor treatment.

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“…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)(2)(3)(4)(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)(7)(8)(9)(10).…”

mentioning

confidence: 99%

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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Limb Regeneration: Induction in the Newborn Opossum

Abstract: The marsupial Didelphys virginiana (the North American opossumn) is uniquely suited for studies of mammalian limb replacement. By transplanting nervous tissute to the limb, regeneration has been successfully induced in this mammal.

Cited by 60 publications

References 16 publications

Modulation of Growth Factor/Cytokine Synthesis and Signaling by 1α,25-Dihydroxyvitamin D3: Implications in Cell Growth and Differentiation

Modulation of Growth Factor/Cytokine Synthesis and Signaling by 1α,25-Dihydroxyvitamin D3: Implications in Cell Growth and Differentiation

BMP signaling induces digit regeneration in neonatal mice

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

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