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Center for Stem Cell Biology and Regenerative Medicine

Division of Stem Cell Aging Medicine
幹細胞加齢医学分野
Professor

Emi K. Nishimura, M.D., Ph.D.

教授

博士（医学）

西村

栄

美Stem cell systems play fundamental roles in sustaining tissue turnover andhomeostasis. Our goal is to understand the mechanisms of tissue aging and cancer
development in mammals and to apply that knowledge to develop strategies toresist against tissue/organ aging, cancer development and other relevant diseases
associated with aging. We further aim to apply this knowledge to drug discovery
and the prevention and treatment of age-associated diseases.

1.  DNA damage types and cell signaling thatcause hair graying and hair thinning
Mohri Y, Nishimura EK, Hayano M1,2, Yang JH1,Oberdoerffer P1, Sinclair DA1.
1
Department of Genetics, Blavatnik Institute, PaulF. Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA, USA; 2Department of Neuropsychiatry, Keio University School ofMedicine, Shinjuku-ku, Tokyo, JapanAll living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost
over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose
their identity, a hallmark of yeast aging. Using a DNA
damage inducing model named “ICE”, we found thatthe induction of DNA double strand breaks (DSBs)
with faithful DNA repair advances the expression ofaging phenotypes with epigenetic changes. Importantly, DNA damage foci are relatively frequently
found in somatic stem cells in the skin during physiological aging. To study the fate and dynamics ofDNA-damaged stem cells in tissues and the resultant
impact in the expression of aging phenotypes, we first
focused on the melanocyte lineage and traced the fateof melanocyte stem cells which acquired DNA DSBs
and demonstrated that those cells disappear from theniche, causing the loss of mature melanocytes for hairpigmentation. This is consistent with our previous report in which we demonstrated that genotoxic stressabrogates renewal of melanocyte stem cells by triggering their ectopic differentiation (Inomata K et al.
Cell, 2009). The aberrant differentiation and the resultant loss of the cell lineage in tissues may partiallyexplain the age-associated loss of lineage-specific epigenetic information in ICE mice. More than that, thefact underlie the fact that cell components in tissues
are being replaced through stem cell differentiationand their eventual depletion. We are currently testingwhether the selective induction of DNA double strand
breaks in melanocyte stem cells similarly causes hairgraying and whether it has some beneficial effects insuppressing melanoma development from the skin.
Similarly, we are testing whether DNA DSBs in hairfollicle stem cells promotes hair thinning and searching for chemicals that can prevent stem cell loss byDNA DSBs.
2.  Fate tracing of DNA-damaged hair follicle stem
cells and their seno-differentiation clearance
out of the niche
Miranda-Salmeron M, Matsumura H, Muroyama
Y, Kato T, Higa M, Tan L, Kawamura Y, Nanba D,
Mohri Y, and Nishimura EK.

155Hair follicles, mammalian mini-organs that grow
hair, miniaturize during aging, leading to hair thining
and loss. In the event of severe genotoxicity such as
DNA double-strand breaks (DSBs), stem cells arelargely believed to choose between cell death (apoptosis) or irreversible cell cycle arrest (senescence) toprevent further damage to neighboring healthy cells
and tissues. Accumulation of these senescent cells
across organs has been implicated in disease and aging-related morbidities such as cancer. However, theexact fate and dynamics of sublethally damaged cells
in tissues during aging/chemotherapy and the development of alopecia - and where exactly senescentcells exist in tissues are still largely unknown becauseof the lack of any single perfect marker of senescentcells. Previous work from our group demonstrated
that various stem cells in the skin will aberrantly commit to differentiation in response to DNA damage byabrogating their self-renewal capabilities to discard
unfit/stressed/aged stem cells. We are testing theunique hypothesis that the tissue youth is achieved
through rapid, dynamic clearance of DNA-damaged
cells out of the epithelia as a robust genomic quality
control mechanism. We are evaluating a combinationof recently devised mouse lines that can induce DSBs
in a small number of stem cells to visualize and trace
the exact fate, senescent state, and dynamics of thoseindividual cells in epithelial tissue such as the hairfollicle. Upon hair follicle stem cell (HFSC) activation,DNA-damaged cells were observed at the epidermal
level, hinting to their transdermal exit out of the niche.
Remarkably, while DNA damaged HFSCs exhibited
gH2AX foci, SAβ-galactosidase activity nor p16 expression was not significantly increased in such cells.
We are in the process of characterizing the identity of
those DNA-damaged HFSCs and their fate switchingin the HFSC niche that leads to hair follicle miniaturization and hair loss. Taken together, our findings
demonstrate a tissue-autonomous mechanism within
the hair follicle niche that can effectively discard
DNA-damaged cells.
3.  Dynamic stem cell selection safeguards thegenomic integrity of the epidermis

Kato T, Liu N, Morinaga H, Asakawa K, Muraguchi
T, Muroyama Y, Shimokawa M, Matsumura H,
Nishimori Y, Tan LJ, Hayano M1,2,3, Sinclair DA1,4,Mohri Y, Nishimura EK. ; 1Department of Genetics,Blavatnik Institute, Paul F. Glenn Center for Biology of Aging Research, Harvard Medical School,Boston, MA, USA; 2Department of Neuropsychiatry, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan; 3Faculty of Science andTechnology, Keio University, Yokohama, Japan;
4Laboratory for Ageing Research, Department ofPharmacology, School of Medical Sciences, The University of New South Wales, Sydney, New South
Wales, Australia
Maintaining genomic integrity and stability is crucial for life; yet, no tissue-driven mechanism that robustly safeguards the epithelial genome has been discovered. Epidermal stem cells (EpiSCs) continuously
replenish the stratified layers of keratinocytes that
protect organisms against various environmentalstresses. To study the dynamics of DNA-damaged
cells in tissues, we devised an in vivo fate tracing system for EpiSCs with DNA double-strand breaks(DSBs) and demonstrated that those cells exit fromtheir niches. Gene expression profiling of EpiSCs withDSBs reveals that DNA damage response (DDR)-p53Notch/p21 axis is specifically induced in EpiSCs withDSBs. Stem cell fate analysis showed that the clearance of EpiSCs with DSBs is caused by selective differentiation and delamination through the DNA
damage response (DDR)-p53-Notch/p21 axis, withthe downregulation of ITGB1. Moreover, concomitantenhancement of symmetric cell divisions of surrounding stem cells indicates that the selective eliminationof cells with DSBs is coupled with the augmented
clonal expansion of intact stem cells. These datacollectively demonstrate that tissue autonomy
through the dynamic coupling of cell-autonomousand non-cell-autonomous mechanisms coordinately
maintains the genomic quality of the epidermis. We
are currently testing the stem cell elimination process
is mediated by cell competition mechanisms and also
whether the phenomenon has any correlation withsystemic aging.

Publications
1.		Yang JH, Hayano M, Griffin PT, Amorim JA, Bonkowski MS, Apostolides JK, Salfati EL, BlanchetteM, Munding EM, Bhakta M, Chew YC, Guo W,
Yang X, Maybury-Lewis S, Tian X, Ross JM, Coppotelli G, Meer MV, Rogers-Hammond R, Vera
DL, Lu YR, Pippin JW, Creswell ML, Dou Z, Xu C,Mitchell SJ, Das A, O’Connell BL, Thakur S, Kane
AE, Su Q, Mohri Y, Nishimura EK, Schaevitz L,Garg N, Balta AM, Rego MA, Gregory-Ksander M,Jakobs TC, Zhong L, Wakimoto H, El Andari J,Grimm D, Mostoslavsky R, Wagers AJ, Tsubota K,Bonasera SJ, Palmeira CM, Seidman JG, Seidman
CE, Wolf NS, Kreiling JA, Sedivy JM, Murphy GF,
Green RE, Garcia BA, Berger SL, Oberdoerffer P,Shankland SJ, Gladyshev VN, Ksander BR, Pfenning AR, Rajman LA, Sinclair DA. Loss of epigenetic information as a cause of mammalian aging.
Cell. 186(2): 305-326, 2023