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Reversible Differentiation of Melanocyte Stem Cells: Designed to Last or Be Lost?

Sun, Qi; Brinks, Anna; Ito, Mayumi
PMID: 37676220
ISSN: 1523-1747
CID: 5607832

Dedifferentiation maintains melanocyte stem cells in a dynamic niche

Sun, Qi; Lee, Wendy; Hu, Hai; Ogawa, Tatsuya; De Leon, Sophie; Katehis, Ioanna; Lim, Chae Ho; Takeo, Makoto; Cammer, Michael; Taketo, M Mark; Gay, Denise L; Millar, Sarah E; Ito, Mayumi
For unknow reasons, the melanocyte stem cell (McSC) system fails earlier than other adult stem cell populations1, which leads to hair greying in most humans and mice2,3. Current dogma states that McSCs are reserved in an undifferentiated state in the hair follicle niche, physically segregated from differentiated progeny that migrate away following cues of regenerative stimuli4-8. Here we show that most McSCs toggle between transit-amplifying and stem cell states for both self-renewal and generation of mature progeny, a mechanism fundamentally distinct from those of other self-renewing systems. Live imaging and single-cell RNA sequencing revealed that McSCs are mobile, translocating between hair follicle stem cell and transit-amplifying compartments where they reversibly enter distinct differentiation states governed by local microenvironmental cues (for example, WNT). Long-term lineage tracing demonstrated that the McSC system is maintained by reverted McSCs rather than by reserved stem cells inherently exempt from reversible changes. During ageing, there is accumulation of stranded McSCs that do not contribute to the regeneration of melanocyte progeny. These results identify a new model whereby dedifferentiation is integral to homeostatic stem cell maintenance and suggest that modulating McSC mobility may represent a new approach for the prevention of hair greying.
PMID: 37076619
ISSN: 1476-4687
CID: 5464522

Solving a molecular cryptogram for the human fingerprint [Comment]

Myung, Peggy; Ito, Mayumi
No two fingerprint patterns are exactly alike. In this issue of Cell, Glover et al. uncover the molecular and cellular mechanisms that result in patterned skin ridges over volar digits. This study reveals that the remarkable diversity of fingerprint configurations may originate from a common patterning code.
PMID: 36868211
ISSN: 1097-4172
CID: 5448572

Wound-Induced Hair Neogenesis Model

Xue, Yingchao; Lim, Chae Ho; Plikus, Maksim V; Ito, Mayumi; Cotsarelis, George; Garza, Luis A
Skin wounds in adult mammals typically heal with a fibrotic scar and fail to restore ectodermal appendages, such as hair follicles or adipose tissue. Intriguingly, new hair follicles regenerate in the center of large full-thickness wounds of mice in a process called wound-induced hair neogenesis (WIHN). WIHN is followed by neogenesis of dermal adipose tissue. Both neogenic events reactivate embryonic-like cellular and molecular programs. The WIHN model provides a platform for studying mammalian regeneration, and findings from this model could instruct future regenerative medicine interventions for treating wounds and alopecia. Since Ito et al. rediscovered WIHN 15 years ago, numerous investigators have worked on the WIHN model using varying wounding protocols and model interpretations. Because a variety of factors, including environmental variables and choice of mouse strains, can affect the outcomes of a WIHN study, the purpose of this article is to provide an overview of the experimental variables that impact WIHN so that experiments between laboratories can be compared in a meaningful manner.
PMID: 36153062
ISSN: 1523-1747
CID: 5333212

Niche stiffness regulates stem cell aging

Lim, Chae Ho; Ito, Mayumi
PMID: 37117779
ISSN: 2662-8465
CID: 5465662

Tracking skin and immune cell interactions

Lim, Chae Ho; Ito, Mayumi
PMID: 33958757
ISSN: 1476-4679
CID: 4878102

Melanoma formation by follicular melanocyte stem cells [Meeting Abstract]

Ito, M; Sun, Q
Melanoma, the most lethal form of skin cancer, is rarely curable at its advanced stages. The early events of this disease, during which treatment would be beneficial, remain poorly elucidated. Melanocyte stem cells (McSCs) residing in the hair follicle niche have been proposed to be a cell-of-origin for melanoma. To understand the cellular and molecular mechanisms regulating the initiation and progression of McSC derived melanoma, we have established a novel c-Kit- CreER-driven melanoma mouse model that enabled us to \target McSCs and trace their oncogenic behaviors. Using this model, we showed that oncogenic McSCs first expand in the niche and then migrate to the epidermis to form epidermal melanoma that later invade into the underlying dermis and undergo metastasis. Furthermore, Wnt and Endothelin signals, secreted by epithelial niche cells during hair anagen onset promoted the malignant transformation of McSCs to melanoma. Finally, transcriptional profiling revealed a strong resemblance between murine McSC-derived melanoma and human melanoma in heterogeneity and gene signatures. These results suggest that follicular McSCs can be an origin of melanoma and that follicular niche can control McSC oncogenic transformation. The similarities of McSC derived melanoma with human melanoma in epidermal to dermal progression, heterogeneity and gene expression suggest the potential utilization of this mouse model as a pre-clinical model for human melanoma
ISSN: 1755-148x
CID: 4828122

Phagocytosis of Wnt inhibitor SFRP4 by late wound macrophages drives chronic Wnt activity for fibrotic skin healing

Gay, Denise; Ghinatti, Giulia; Guerrero-Juarez, Christian F; Ferrer, Rubén A; Ferri, Federica; Lim, Chae Ho; Murakami, Shohei; Gault, Nathalie; Barroca, Vilma; Rombeau, Isabelle; Mauffrey, Philippe; Irbah, Lamya; Treffeisen, Elsa; Franz, Sandra; Boissonnas, Alexandre; Combadière, Christophe; Ito, Mayumi; Plikus, Maksim V; Romeo, Paul-Henri
Human and murine skin wounding commonly results in fibrotic scarring, but the murine wounding model wound-induced hair neogenesis (WIHN) can frequently result in a regenerative repair response. Here, we show in single-cell RNA sequencing comparisons of semi-regenerative and fibrotic WIHN wounds, increased expression of phagocytic/lysosomal genes in macrophages associated with predominance of fibrotic myofibroblasts in fibrotic wounds. Investigation revealed that macrophages in the late wound drive fibrosis by phagocytizing dermal Wnt inhibitor SFRP4 to establish persistent Wnt activity. In accordance, phagocytosis abrogation resulted in transient Wnt activity and a more regenerative healing. Phagocytosis of SFRP4 was integrin-mediated and dependent on the interaction of SFRP4 with the EDA splice variant of fibronectin. In the human skin condition hidradenitis suppurativa, phagocytosis of SFRP4 by macrophages correlated with fibrotic wound repair. These results reveal that macrophages can modulate a key signaling pathway via phagocytosis to alter the skin wound healing fate.
PMID: 32219160
ISSN: 2375-2548
CID: 4394842

Oncogenic melanocyte stem cells, driven by regenerative niche signals, give rise to heterogeneous melanoma resembling human melanoma [Meeting Abstract]

Sun, Q.; Katehis, I.; Lee, W.; Mohri, Y.; Takeo, M.; Lim, C.; Xu, X.; Myung, P. S.; Atit, R.; Taketo, M.; Moubarak, R.; Schober, M.; Osman, I.; Gay, D.; Saur, D.; Nishimura, E. K.; Ito, M.
ISSN: 0022-202x
CID: 4560342

The Seed Tends to the Soil: Hair Follicle Stem Cells Remodel Their Lymphatic Niche

Gay, Denise; Ito, Mayumi
Hair follicle stem cells may themselves regulate the niche environment for hair follicle regrowth. A recent Science paper from Elaine Fuchs and colleagues (Gur-Cohen et al., 2019) suggests that this involves regulation of the lymphatic system and may have implications in understanding tissue regeneration.
PMID: 31809735
ISSN: 1875-9777
CID: 4230362