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Gremlin 2 suppresses differentiation of stem/progenitor cells in the human skin

INTRODUCTION: The skin is comprised of various kinds of cells and has three layers, the epidermis, dermis and subcutaneous adipose tissue. Stem cells in each tissue duplicate themselves and differentiate to supply new cells that function in the tissue, and thereby maintain the tissue homeostasis. In...

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Autores principales: Kawagishi-Hotta, Mika, Hasegawa, Seiji, Inoue, Yu, Hasebe, Yuichi, Arima, Masaru, Iwata, Yohei, Sugiura, Kazumitsu, Akamatsu, Hirohiko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Japanese Society for Regenerative Medicine 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280529/
https://www.ncbi.nlm.nih.gov/pubmed/34307797
http://dx.doi.org/10.1016/j.reth.2021.06.007
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author Kawagishi-Hotta, Mika
Hasegawa, Seiji
Inoue, Yu
Hasebe, Yuichi
Arima, Masaru
Iwata, Yohei
Sugiura, Kazumitsu
Akamatsu, Hirohiko
author_facet Kawagishi-Hotta, Mika
Hasegawa, Seiji
Inoue, Yu
Hasebe, Yuichi
Arima, Masaru
Iwata, Yohei
Sugiura, Kazumitsu
Akamatsu, Hirohiko
author_sort Kawagishi-Hotta, Mika
collection PubMed
description INTRODUCTION: The skin is comprised of various kinds of cells and has three layers, the epidermis, dermis and subcutaneous adipose tissue. Stem cells in each tissue duplicate themselves and differentiate to supply new cells that function in the tissue, and thereby maintain the tissue homeostasis. In contrast, senescent cells accumulate with age and secrete senescence-associated secretory phenotype (SASP) factors that impair surrounding cells and tissues, which lowers the capacity to maintain homeostasis in each tissue. Previously, we found Gremlin 2 (GREM2) as a novel SASP factor in the skin and reported that GREM2 suppressed the differentiation of adipose-derived stromal/stem cells. In the present study, we investigated the effects of GREM2 on stem cells in the epidermis and dermis. METHODS: To examine whether GREM2 expression and the differentiation levels in the epidermis and dermis are correlated, the expressions of GREM2, stem cell markers, an epidermal differentiation marker Keratin 10 (KRT10) and a dermal differentiation marker type 3 procollagen were examined in the skin samples (n = 14) randomly chosen from the elderly where GREM2 expression level is high and the individual differences of its expression are prominent. Next, to test whether GREM2 affects the differentiation of skin stem cells, cells from two established lines (an epidermal and a dermal stem/progenitor cell model) were cultured and induced to differentiate, and recombinant GREM2 protein was added. RESULTS: In the human skin, the expression levels of GREM2 varied among individuals both in the epidermis and dermis. The expression level of GREM2 was not correlated with the number of stem cells, but negatively correlated with those of both an epidermal and a dermal differentiation markers. The expression levels of epidermal differentiation markers were significantly suppressed by the addition of GREM2 in the three-dimensional (3D) epidermis generated with an epidermal stem/progenitor cell model. In addition, by differentiation induction, the expressions of dermal differentiation markers were induced in cells from a dermal stem/progenitor cell model, and the addition of GREM2 significantly suppressed the expressions of the dermal differentiation markers. CONCLUSIONS: GREM2 expression level did not affect the numbers of stem cells in the epidermis and dermis but affects the differentiation and maturation levels of the tissues, and GREM2 suppressed the differentiation of stem/progenitor cells in vitro. These findings suggest that GREM2 may contribute to the age-related reduction in the capacity to maintain skin homeostasis by suppressing the differentiation of epidermal and dermal stem/progenitor cells.
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spelling pubmed-82805292021-07-22 Gremlin 2 suppresses differentiation of stem/progenitor cells in the human skin Kawagishi-Hotta, Mika Hasegawa, Seiji Inoue, Yu Hasebe, Yuichi Arima, Masaru Iwata, Yohei Sugiura, Kazumitsu Akamatsu, Hirohiko Regen Ther Original Article INTRODUCTION: The skin is comprised of various kinds of cells and has three layers, the epidermis, dermis and subcutaneous adipose tissue. Stem cells in each tissue duplicate themselves and differentiate to supply new cells that function in the tissue, and thereby maintain the tissue homeostasis. In contrast, senescent cells accumulate with age and secrete senescence-associated secretory phenotype (SASP) factors that impair surrounding cells and tissues, which lowers the capacity to maintain homeostasis in each tissue. Previously, we found Gremlin 2 (GREM2) as a novel SASP factor in the skin and reported that GREM2 suppressed the differentiation of adipose-derived stromal/stem cells. In the present study, we investigated the effects of GREM2 on stem cells in the epidermis and dermis. METHODS: To examine whether GREM2 expression and the differentiation levels in the epidermis and dermis are correlated, the expressions of GREM2, stem cell markers, an epidermal differentiation marker Keratin 10 (KRT10) and a dermal differentiation marker type 3 procollagen were examined in the skin samples (n = 14) randomly chosen from the elderly where GREM2 expression level is high and the individual differences of its expression are prominent. Next, to test whether GREM2 affects the differentiation of skin stem cells, cells from two established lines (an epidermal and a dermal stem/progenitor cell model) were cultured and induced to differentiate, and recombinant GREM2 protein was added. RESULTS: In the human skin, the expression levels of GREM2 varied among individuals both in the epidermis and dermis. The expression level of GREM2 was not correlated with the number of stem cells, but negatively correlated with those of both an epidermal and a dermal differentiation markers. The expression levels of epidermal differentiation markers were significantly suppressed by the addition of GREM2 in the three-dimensional (3D) epidermis generated with an epidermal stem/progenitor cell model. In addition, by differentiation induction, the expressions of dermal differentiation markers were induced in cells from a dermal stem/progenitor cell model, and the addition of GREM2 significantly suppressed the expressions of the dermal differentiation markers. CONCLUSIONS: GREM2 expression level did not affect the numbers of stem cells in the epidermis and dermis but affects the differentiation and maturation levels of the tissues, and GREM2 suppressed the differentiation of stem/progenitor cells in vitro. These findings suggest that GREM2 may contribute to the age-related reduction in the capacity to maintain skin homeostasis by suppressing the differentiation of epidermal and dermal stem/progenitor cells. Japanese Society for Regenerative Medicine 2021-07-12 /pmc/articles/PMC8280529/ /pubmed/34307797 http://dx.doi.org/10.1016/j.reth.2021.06.007 Text en © 2021 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Kawagishi-Hotta, Mika
Hasegawa, Seiji
Inoue, Yu
Hasebe, Yuichi
Arima, Masaru
Iwata, Yohei
Sugiura, Kazumitsu
Akamatsu, Hirohiko
Gremlin 2 suppresses differentiation of stem/progenitor cells in the human skin
title Gremlin 2 suppresses differentiation of stem/progenitor cells in the human skin
title_full Gremlin 2 suppresses differentiation of stem/progenitor cells in the human skin
title_fullStr Gremlin 2 suppresses differentiation of stem/progenitor cells in the human skin
title_full_unstemmed Gremlin 2 suppresses differentiation of stem/progenitor cells in the human skin
title_short Gremlin 2 suppresses differentiation of stem/progenitor cells in the human skin
title_sort gremlin 2 suppresses differentiation of stem/progenitor cells in the human skin
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280529/
https://www.ncbi.nlm.nih.gov/pubmed/34307797
http://dx.doi.org/10.1016/j.reth.2021.06.007
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