GOPAKUMAR CHANGARATHIL

Tsukuba Repository

Wild-type and SAMP1/8 mice show age dependent
changes in distinct stem cell compartments of
the interfollicular epidermis
著者（英） GOPAKUMAR CHANGARATHIL
year 2019
その他のタイトル 野生型老齢マウスと老化促進マウス（SAMP1/8）を
用いた表皮幹細胞の老化表現型の解析
学位授与大学 筑波大学 (University of Tsukuba)
学位授与年度 2019
報告番号 12102甲第9297号
URL http://hdl.handle.net/2241/00158127
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氏     名 CHANGARATHIL GOPAKUMAR 
学 位 の 種 類        博士（医学） 
学 位 記 番 号        博甲第 ９２９７ 号 
学位授与年月        令和元年９月２５日 
学位授与の要件        学位規則第４条第１項該当 
審 査 研 究 科        人間総合科学研究科 
学位論文題目        Wild-type and SAMP1/8 mice show age dependent changes in  
                 distinct stem cell compartments of the interfollicular epidermis 
（野生型老齢マウスと老化促進マウス（SAMP1/8）を用いた 
表皮幹細胞の老化表現型の解析） 
主 査            筑波大学教授 医学博士     加藤 光保     
副 査          筑波大学教授 博士（医学）    大根田 修 
副 査          筑波大学教授 博士（生物科学）村谷 匡史   
副 査          筑波大学准教授 博士（医学）  藤澤 康弘 
 
 
論文の内容の要旨 
Abstract of thesis 
 
In this doctoral dissertation, CHANGARATHIL GOPAKUMAR describes the aging of the heterogeneous stem cell 
populations in the mouse interfollicular epidermis. The summary is as follows: 
 
（目的 Purpose） 
Delayed wound healing and reduced barrier function with an increased risk of cancer are characteristics of aged skin 
and one possible mechanism is misregulation or dysfunction of epidermal stem cells during aging. Recent studies 
have identified heterogenous stem cell populations in the mouse interfollicular epidermis that are defined by territorial 
distribution and cell division frequency; however, it is largely unknown whether individual stem cell populations 
undergo distinct aging process. In this research, the author aims to understand the cellular and molecular basis of 
stem cell aging in the mouse epidermis with a special focus on two populations of stem cells that divide at different 
rates. 
 
（対象と方法 Materials and Methods） 
The author chose the tail epidermis as a model to study the stem cell aging, because of the presence of regionally-
defined scale and interscale structures, corresponding to the localization of slow-cycling and fast-dividing stem cells, 
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respectively. C57BL6/J wild-type mice at ages of 2 months (young) and 2 years (old), as well as SAMR, SAMP1 and 
SAMP8 mice at 6 months and 1 year of age were used for the aging phenotype characterization. Young and old H2B-
GFP tet-off mice were used to study the proliferation history, cell isolation and the transcriptome analysis of slow-
cycling and fast-dividing stem cells in the interfollicular epidermis. 
 
（結果 Results） 
The epidermis exhibited structural changes such as irregular undulations and overall thinning of the tissue in old 
wild-type mice. In the old epidermis, proliferation was preferentially decreased in the region where fast-dividing 
stem cells reside whereas the lineage differentiation marker appeared to be more affected in the slow-cycling stem 
cell region. The quantitative analysis of proliferation history by using H2B-GFP tet-off system further supported that 
in the old epidermis, all the basal cells were slower-cycling compared to the ones in the young epidermis. Furthermore, 
the author noted that SAMP8, but not SAMP1, exhibited precocious aging similar to that of aged wild-type mice at 
one year of age, suggesting a potential use of this model for aging study of the epidermis and its stem cells. Finally, 
by means of RNA sequencing of slow-cycling and fast-dividing stem cells, the author demonstrated that genes related 
to extracellular matrix and cellular metabolism were overrepresented in the aged stem cells. 
 
（考察 Discussion） 
The author discusses that while previous studies pointed out that young and old epidermis are transcriptionally and 
architecturally similar, this study here provides evidences regarding the age-dependent changes in the murine 
epidermis. Slow-cycling and fast-dividing stem cells of the epidermis seem to be affected in different aspects of tissue 
maintenance: differentiation process appears to be affected in the slow-cycling stem cell lineage, whereas 
proliferation is affected in fast-dividing stem cells. Moreover, the author emphasizes that gene expression profiling 
between young and old epidermal stem cells revealed specific gene sets which are up- or down-regulated during 
aging, pointing out that the aged epidermis exhibits transcriptional changes at the stem cell level. 
 Taken together, the author considers that this study revealed distinct aging processes governing the two 
epidermal stem cell populations, and suggested a potential mechanism in differential responses of compartmentalized 
stem cells and their niche to aging. 
 
審査の結果の要旨 
 Abstract of assessment result 
 
（批評 General Comments） 
Changarathil Gopakumar examined the differences in proliferative potencies and gene expression profiles of two 
distinct interfollicular stem cells in young and old mice epidermis. He found the differences of aged phenotypes 
between two stem cell populations: i.e., changes in the differentiation process of the slow-cycling stem cell lineage 
and in the proliferation of fast-dividing stem cells. He further found that SAMP8 but not SAMP1 mice exhibit 
precocious aging similar to that of aged wild-type mice. The research is original and appropriately designed. Data 
are clear and convincing and the discussion is reasonable. The thesis paper is carefully written with a suitable style. 
 
（最終試験の結果 Assessment） 
The final examination committee conducted a meeting as a final examination on June 17, 2019. The applicant 
provided an overview of dissertation, addressed questions and comments raised during Q&A session. All of the 
committee members reached a final decision that the applicant has passed the final examination. 
 
（結論 Conclusion） 
The final examination committee approved that the applicant is qualified to be awarded Doctor of Philosophy in 
Medical Sciences. 


野生型老齢マウスと老化促進マウス（SAMP1/8）を用いた表皮幹細胞の老化表現型の解析

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野生型老齢マウスと老化促進マウス（SAMP1/8）を用いた表皮幹細胞の老化表現型の解析

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