Keratinocyte growth factor protects epidermis and hair follicles from cell death induced by UV irradiation, chemotherapeutic or cytotoxic agents

Braun, Susanne; Krampert, Monika; Bodó, Enikő; Kümin, Angelika; Born-Berclaz, Christiane; Paus, Ralf; Werner, Sabine

doi:10.1242/jcs.03259

Cited by 77 publications

(73 citation statements)

References 52 publications

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“…6,9,11,13 Because of the very limited availability of human scalp HFs for these experiments, only one selected dose of KGF could be studied, which we had previously demonstrated to counteract significantly menadione-induced HF toxicity. 44 …”

Section: Hf Organ Culturementioning

confidence: 99%

“…Therefore, we opted for ideally studying the cytoprotective growth factor KGF (keratinocyte growth factor, fibroblast growth factor-7), because it strongly reduces CIA in mice, 41 is a potent survival factor for epithelial cells in vivo, 42,43 and inhibits massive apoptosis induced by reactive oxygen species, both in human keratinocytes in vitro and in organ-cultured human HFs. 44 …”

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confidence: 99%

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Dissecting the Impact of Chemotherapy on the Human Hair Follicle

Bodó

Tobin

Kamenisch

et al. 2007

The American Journal of Pathology

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106

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Chemotherapy-induced alopecia represents one of the major unresolved problems of clinical oncology. The underlying molecular pathogenesis in humans is virtually unknown because of the lack of adequate research models. Therefore, we have explored whether microdissected, organ-cultured, human scalp hair follicles (HFs) in anagen VI can be exploited for dissecting and manipulating the impact of chemotherapy on human HFs. Here, we show that these organ-cultured HFs respond to a key cyclophosphamide metabolite, 4-hydroperoxycyclophosphamide (4-HC), in a manner that resembles chemotherapy-induced HF dystrophy as it occurs in vivo: namely, 4-HC induced melanin clumping and melanin incontinence, down-regulated keratinocyte proliferation, massively up-regulated apoptosis of hair matrix keratinocytes, prematurely induced catagen, and up-regulated p53. In addition, 4-HC induced DNA oxidation and the mitochondrial DNA common deletion. The organ culture system facilitated the identification of new molecular targets for chemotherapyinduced HF damage by microarray technology (eg, interleukin-8, fibroblast growth factor-18, and glypican 6). It was also used to explore candidate chemotherapy protectants, for which we used the cytoprotective cytokine keratinocyte growth factor as exemplary pilot agent. Thus, this novel system serves as a powerful yet pragmatic tool for dissecting and manipulating the impact of chemotherapy on the human HF. (Am J Pathol

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Section: Hf Organ Culturementioning

confidence: 99%

mentioning

confidence: 99%

Dissecting the Impact of Chemotherapy on the Human Hair Follicle

Bodó

Tobin

Kamenisch

et al. 2007

The American Journal of Pathology

Self Cite

106

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“…normal skin development and wound healing (Petiot et al 2003;Beer et al 2005;Komi-Kuramochi et al 2005;Braun et al 2006;Nagy et al 2006). Along with certain FGF isoforms, PDGF family members can also be potent adipocyte mitogens (Schmidt et al 1990;Hua et al 2004).…”

Section: The Journal Of Histochemistry and Cytochemistrymentioning

confidence: 99%

NG2 Proteoglycan Expression in Mouse Skin: Altered Postnatal Skin Development in the NG2 Null Mouse

Kadoya

Fukushi

Matsumoto

et al. 2007

J Histochem Cytochem.

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S U M M A R Y In early postnatal mouse skin, the NG2 proteoglycan is expressed in the subcutis, the dermis, the outer root sheath of hair follicles, and the basal keratinocyte layer of the epidermis. With further development, NG2 is most prominently expressed by stem cells in the hair follicle bulge region, as also observed in adult human skin. During telogen and anagen phases of the adult hair cycle, NG2 is also found in stem cell populations that reside in dermal papillae and the outer root sheaths of hair follicles. Ablation of NG2 produces alterations in both the epidermis and subcutis layers of neonatal skin. Compared with wild type, the NG2 null epidermis does not achieve its full thickness due to reduced proliferation of basal keratinocytes that serve as the stem cell population in this layer. Thickening of the subcutis is also delayed in NG2 null skin due to deficiencies in the adipocyte population. (J Histochem Cytochem 56:295-303, 2008)

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“…Mucosal epithelial growth factors such as keratinocyte growth factor (KGF) have been shown to be efficacious in treating experimental animal models of chemotherapy or radiotherapy-induced oral mucositis, and is the first approved biologic therapy for human cancer patients with oral mucositis (14)(15)(16)(17)(18)(19)(20). However, KGF has been shown to enhance the growth of human epithelial tumor cell lines in vitro and to increase the rate of tumor cell growth in human carcinoma xenograft models, probably by binding to its receptor present on the surface of these cells (21).…”

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confidence: 99%

R-Spondin1 protects mice from chemotherapy or radiation-induced oral mucositis through the canonical Wnt/β-catenin pathway

Zhao¹,

Kim²,

Vera³

et al. 2009

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

108

100

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R-Spondin1 (RSpo1) is a novel secreted protein that augments canonical Wnt/␤-catenin signaling. We injected recombinant RSpo1 protein into transgenic Wnt reporter TOPGAL mice and have identified the oral mucosa as a target tissue for RSpo1. Administration of RSpo1 into normal mice triggered nuclear translocation of ␤-catenin and resulted in increased basal layer cellularity, thickened mucosa, and elevated epithelial cell proliferation in tongue. We herein evaluated the therapeutic potential of RSpo1 in treating chemotherapy or radiotherapyinduced oral mucositis in several mouse models. Prophylactic treatment with RSpo1 dose-dependently overcame the reduction of basal layer epithelial cellularity, mucosal thickness, and epithelial cell proliferation in tongues of mice exposed to whole-body irradiation. RSpo1 administration also substantially alleviated tongue mucositis in the oral cavity of mice receiving concomitant 5-fluorouracil and x-ray radiation. Furthermore, RSpo1 significantly reduced the extent of tongue ulceration in mice receiving a single fraction, high dose head-only radiation in a dose-dependent manner. Moreover, combined therapy of RSpo1 and keratinocyte growth factor resulted in complete healing of tongue ulcers in mice subjected to snout-only irradiation. In conclusion, our results demonstrate RSpo1 to be a potent therapeutic agent for oral mucositis by enhancing basal layer epithelial regeneration and accelerating mucosal repair through upregulation of Wnt/␤-catenin pathway.RSpo1 ͉ tongue ulceration ͉ head-only radiation ͉ TOPGAL ͉ 5-FU

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Keratinocyte growth factor protects epidermis and hair follicles from cell death induced by UV irradiation, chemotherapeutic or cytotoxic agents

Cited by 77 publications

References 52 publications

Dissecting the Impact of Chemotherapy on the Human Hair Follicle

Dissecting the Impact of Chemotherapy on the Human Hair Follicle

NG2 Proteoglycan Expression in Mouse Skin: Altered Postnatal Skin Development in the NG2 Null Mouse

R-Spondin1 protects mice from chemotherapy or radiation-induced oral mucositis through the canonical Wnt/β-catenin pathway

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