Mitochondrial Reactive Oxygen Species Promote Epidermal Differentiation and Hair Follicle Development

Hamanaka, Robert B.; Glasauer, Andrea; Hoover, Paul; Yang, Shuangni; Blatt, Hanz; Mullen, Andrew R.; Getsios, Spiro; Gottardi, Cara J.; DeBerardinis, Ralph J.; Lavker, Robert M.; Chandel, Navdeep S.

doi:10.1126/scisignal.2003638

Cited by 261 publications

(264 citation statements)

References 56 publications

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“…The signaling pathways associated with this phenomenon are incompletely understood. However, mitochondrial oxidative stress was shown to promote epidermal differentiation in mice (40) and in culture (41), as did uncoupled mitochondria (42). Our studies of constitutive Sod2-deficient mice also showed increased keratinocyte differentiation (19), but early lethality complicated interpretation of this result.…”

Section: Discussionmentioning

confidence: 50%

Pleiotropic age-dependent effects of mitochondrial dysfunction on epidermal stem cells

Velarde

Demaria

Melov

et al. 2015

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

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Tissue homeostasis declines with age partly because stem/progenitor cells fail to self-renew or differentiate. Because mitochondrial damage can accelerate aging, we tested the hypothesis that mitochondrial dysfunction impairs stem cell renewal or function. We developed a mouse model, Tg(KRT14-cre/Esr1) 20Efu/J × Sod2 tm1Smel , that generates mitochondrial oxidative stress in keratin 14-expressing epidermal stem/progenitor cells in a temporally controlled manner owing to deletion of Sod2, a nuclear gene that encodes the mitochondrial antioxidant enzyme superoxide dismutase 2 (Sod2). Epidermal Sod2 loss induced cellular senescence, which irreversibly arrested proliferation in a fraction of keratinocytes. Surprisingly, in young mice, Sod2 deficiency accelerated wound closure, increasing epidermal differentiation and reepithelialization, despite the reduced proliferation. In contrast, at older ages, Sod2 deficiency delayed wound closure and reduced epidermal thickness, accompanied by epidermal stem cell exhaustion. In young mice, Sod2 deficiency accelerated epidermal thinning in response to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate, phenocopying the reduced regeneration of older Sod2-deficient skin. Our results show a surprising beneficial effect of mitochondrial dysfunction at young ages, provide a potential mechanism for the decline in epidermal regeneration at older ages, and identify a previously unidentified age-dependent role for mitochondria in skin quality and wound closure.

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Section: Discussionmentioning

confidence: 50%

Pleiotropic age-dependent effects of mitochondrial dysfunction on epidermal stem cells

Velarde

Demaria

Melov

et al. 2015

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

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“…Although ROS have long been known for their damage-promoting detrimental effects, their roles as signaling molecules are now becoming better understood (Shadel and Horvath, 2015). In particular, mitochondrial ROS (mtROS) signaling has also been implicated in homeostatic processes, including cellular differentiation (Hamanaka and Chandel, 2010;Tormos et al, 2011;Hamanaka et al, 2013). A recent study demonstrated that multipotent neural progenitors maintain a high level of ROS (Le Belle et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Prdm16 is crucial for progression of the multipolar phase during neural differentiation of the developing neocortex

et al. 2017

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The precise control of neuronal migration and morphological changes during differentiation is essential for neocortical development. We hypothesized that the transition of progenitors through progressive stages of differentiation involves dynamic changes in levels of mitochondrial reactive oxygen species (mtROS), depending on cell requirements. We found that progenitors had higher levels of mtROS, but that these levels were significantly decreased with differentiation. The Prdm16 gene was identified as a candidate modulator of mtROS using microarray analysis, and was specifically expressed by progenitors in the ventricular zone. However, Prdm16 expression declined during the transition into NeuroD1-positive multipolar cells. Subsequently, repression of Prdm16 expression by NeuroD1 on the periphery of ventricular zone was crucial for appropriate progression of the multipolar phase and was required for normal cellular development. Furthermore, time-lapse imaging experiments revealed abnormal migration and morphological changes in Prdm16-overexpressing and -knockdown cells. Reporter assays and mtROS determinations demonstrated that PGC1α is a major downstream effector of Prdm16 and NeuroD1, and is required for regulation of the multipolar phase and characteristic modes of migration. Taken together, these data suggest that Prdm16 plays an important role in dynamic cellular redox changes in developing neocortex during neural differentiation.

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“…ROS have been implicated in a variety of processes such as reducing lifespan of hematopoietic stem cells, 89 inducing insulin resistance in adipocytes, 90 and regulating Notch signaling in epidermal cell differentiation. 91 Recent work comparing chain addition and thiol-ene polymerizations for encapsulation of primary chondrocytes shows that increased ROS exposure resulting from chain addition polymerizations leads to hypertrophic chondrocyte phenotypes similar to pathologic chondrocytes observed in osteoarthritis. In contrast, the phenotypes of chondrocytes encapsulated using a thiol-ene polymerization resemble those present in hyaline cartilage.…”

Section: Resultsmentioning

confidence: 99%

Development of Poly(Ethylene Glycol) Hydrogels for Salivary Gland Tissue Engineering Applications

Shubin

Felong

Graunke

et al. 2015

Tissue Engineering Part A

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More than 40,000 patients are diagnosed with head and neck cancers annually in the United States with the vast majority receiving radiation therapy. Salivary glands are irreparably damaged by radiation therapy resulting in xerostomia, which severely affects patient quality of life. Cell-based therapies have shown some promise in mouse models of radiation-induced xerostomia, but they suffer from insufficient and inconsistent gland regeneration and accompanying secretory function. To aid in the development of regenerative therapies, poly(ethylene glycol) hydrogels were investigated for the encapsulation of primary submandibular gland (SMG) cells for tissue engineering applications. Different methods of hydrogel formation and cell preparation were examined to identify cytocompatible encapsulation conditions for SMG cells. Cell viability was much higher after thiol-ene polymerizations compared with conventional methacrylate polymerizations due to reduced membrane peroxidation and intracellular reactive oxygen species formation. In addition, the formation of multicellular microspheres before encapsulation maximized cell-cell contacts and increased viability of SMG cells over 14-day culture periods. Thiol-ene hydrogel-encapsulated microspheres also promoted SMG proliferation. Lineage tracing was employed to determine the cellular composition of hydrogel-encapsulated microspheres using markers for acinar (Mist1) and duct (Keratin5) cells. Our findings indicate that both acinar and duct cell phenotypes are present throughout the 14 day culture period. However, the acinar:duct cell ratios are reduced over time, likely due to duct cell proliferation. Altogether, permissive encapsulation methods for primary SMG cells have been identified that promote cell viability, proliferation, and maintenance of differentiated salivary gland cell phenotypes, which allows for translation of this approach for salivary gland tissue engineering applications.

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Mitochondrial Reactive Oxygen Species Promote Epidermal Differentiation and Hair Follicle Development

Cited by 261 publications

References 56 publications

Pleiotropic age-dependent effects of mitochondrial dysfunction on epidermal stem cells

Pleiotropic age-dependent effects of mitochondrial dysfunction on epidermal stem cells

Prdm16 is crucial for progression of the multipolar phase during neural differentiation of the developing neocortex

Development of Poly(Ethylene Glycol) Hydrogels for Salivary Gland Tissue Engineering Applications

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