- Email: [email protected]
Tregs Expand the Skin Stem Cell Niche
Developmental Cell
Previews Tregs Expand the Skin Stem Cell Niche Valerie Horsley1,* and Shruti Naik2 1Departments
of Molecular, Cellular and Developmental Biology and Dermatology, Yale University, New Haven, CT 06520, USA of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10065, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.devcel.2017.05.020 2Laboratory
Regulatory T cells (Tregs) are emerging as an essential stem cell niche component that promotes wound repair in adipose, muscle, and lung tissues. Recently in Cell, Ali et al. (2017) report that skin resident Tregs facilitate the proliferation and differentiation of hair follicle stem cells through Notch signaling. Hair follicle stem cells (HFSCs) reside in a specialized niche called the bulge and are essential for the cyclic regeneration of the hair follicle. Following hair follicle morphogenesis, the growing hair follicle ceases hair production and regresses (death phase, catagen), and only the stem cells in the bulge region of the follicle remain. The HFSCs remain dormant during the resting phase (telogen) of the hair cycle. When bulge stem cells become activated at the start of the next anagen, they exit the bulge niche, moving downward to produce highly proliferative progenitor cells at the base of the follicle in the hair germ (Zhang et al., 2009). The activation and physiology of HFSCs is tightly controlled by signals emanating from the dermis. By interacting directly or indirectly with the bulge at discrete phases of the hair follicle cycle, niche cells coordinate the cyclic generation and destruction of this tissue (Goldstein and Horsley, 2012; Hsu et al., 2014). For instance, the transition from quiescence to activation is dependent upon factors such as WNTs, fibroblast growth factors (FGFs), TGFb2, and PDGFa produced by the dermal papillae and adipocyte lineage, as well as neural and smooth muscle cells. A myriad of immune cells, including Foxp3+ regulatory T cells (Tregs), reside in close apposition to the hair follicle (Ali et. al 2017). Tregs are essential for counteracting inflammatory T cells, thus limiting immunopathology and promoting skin homeostasis. Despite their proximity and prevalence, the contribution of Tregs to HFSC activation was unknown. The paper from Ali et al. (2017) now shows that Tregs contribute to HFSC activation by promoting their proliferation and differentiation. An emerging role for Tregs beyond immune regulation has been reported in
more, genome-wide association studies have linked Tregs to hair follicle degeneration during alopecia areata (Petukhova et al., 2010). These studies have shed light on the repair function of Treg cells, and yet how these cells homeostatically maintain tissue integrity remains an open question. A recent study by Rosenblum and colleagues in Cell (Ali et al., 2017) has shed light on exactly how Tregs direct HFSC
the context of tissue repair (Arpaia et al., 2015; Burzyn et al., 2013). Tregs elaborate on the repertoire of tissue mediators to perform their non-canonical wound repair functions. For instance, lung and muscle Tregs express the EGFR ligand Amphiregulin to promote repair. Similarly, Tregs localize to the skin postnatally, where they have been shown to regulate wound healing (Nosbaum et al., 2016). Further-
Skin Anagen (active)
Telogen (quiescent) Inhibit Epidermal Fate
Notch activation
WNTS? BMP inhibitor FGF7/10 TGFβ2
Pro Dif liferat fere io ntia n tion
JAG1+ Treg α GF
PD
Upstream regulators of JAG1?
Hair Follicle Stem Cell JAG1positive Skin Treg JAG1negative Lymph Node Treg Adipocyte Precursor Cell Fibroblast Dermal Papillae
Lymph Node
Figure 1. JAG1+ Tregs-Induced HFSC Activation
Ali et al. (2017) report a role for JAG1+ skin regulatory T cells (Tregs) in promoting HFSC proliferation and differentiation via Notch signaling during the transition from telogen (quiescence) to anagen (activation).
Developmental Cell 41, June 5, 2017 ª 2017 Elsevier Inc. 455
Developmental Cell
Previews activation and, consequently, the HF cycle. The authors show that Tregs increase in the skin’s dermis prior to activation of hair follicle stem cells and localize adjacent to bulge stem cells. Importantly, ablation of Tregs completely abrogates the ability of the hair follicle to regenerate, implicating Tregs as a key component of the skin stem cell niche. Probing the molecular mechanism for this interaction, the authors compared mRNA expression of Tregs purified from the skin with Tregs isolated from lymph nodes to uncover the specific enrichment of the Notch ligand Jag1 in bulge-associated Tregs. Consistently, Notch target genes were reduced in HFSCs when Tregs were depleted. Beads coated with Jag1 were able to rescue the activation of the HFSCs in mice lacking Tregs, and conditional deletion of Jag1 from Tregs resulted in defects in activation of HFSCs. Together, these data highlight Tregsderived Jag1+ as a source of activating signals for HFSCs and add to our understanding of Notch signals in regulating HFSCs (Figure 1) (Blanpain et al., 2007). How Jag1 expression is regulated in Tregs and whether expression requires
T cell receptor engagement, interaction with HFSCs, and/or other niche components remains to be determined. Notch signaling underlies several aspects of cellular differentiation in interfollicular and follicular keratinocytes (Blanpain et al., 2007). How Treg-expressed Jag1 may contribute to regulation of these cells or other epidermal stem cells subsets, as well as their differentiated progeny, will be an intriguing future line of inquiry. Additionally, Notch signaling has been shown to have tumor-suppressive functions in the skin (Demehri et al., 2009), raising the possibility that Jag1 expression on Tregs contributes to tumor suppression. Jag1+ Tregs may thus promote tissue homeostasis by multiple mechanisms. Beyond the skin, it is tempting to speculate that Tregs similarly localize to and interact with stem cell niches in a range of tissues and via microenvironment-specific factors such as Jag1 to regulate the parenchyma at steady state.
Lowe, M.M., et al. (2017). Cell 169, 1119– 1129. Arpaia, N., Green, J.A., Moltedo, B., Arvey, A., Hemmers, S., Yuan, S., Treuting, P.M., and Rudensky, A.Y. (2015). Cell 162, 1078–1089. Blanpain, C., Horsley, V., and Fuchs, E. (2007). Cell 128, 445–458. Burzyn, D., Kuswanto, W., Kolodin, D., Shadrach, J.L., Cerletti, M., Jang, Y., Sefik, E., Tan, T.G., Wagers, A.J., Benoist, C., and Mathis, D. (2013). Cell 155, 1282–1295. Demehri, S., Turkoz, A., and Kopan, R. (2009). Cancer Cell 16, 55–66. Goldstein, J., and Horsley, V. (2012). Cell. Mol. Life Sci. 69, 2573–2582. Hsu, Y.C., Li, L., and Fuchs, E. (2014). Nat. Med. 20, 847–856. Nosbaum, A., Prevel, N., Truong, H.A., Mehta, P., Ettinger, M., Scharschmidt, T.C., Ali, N.H., Pauli, M.L., Abbas, A.K., and Rosenblum, M.D. (2016). J. Immunol. 196, 2010–2014. Petukhova, L., Duvic, M., Hordinsky, M., Norris, D., Price, V., Shimomura, Y., Kim, H., Singh, P., Lee, A., Chen, W.V., et al. (2010). Nature 466, 113–117.
REFERENCES Ali, N., Zirak, B., Rodriguez, R.S., Pauli, M.L., Truong, H.-A., Lai, K., Ahn, R., Corbin, K.,
Zhang, Y.V., Cheong, J., Ciapurin, N., McDermitt, D.J., and Tumbar, T. (2009). Cell Stem Cell 5, 267–278.
R-spondin Is More Than Just Wnt’s Sidekick David J. Huels1,2 and Owen J. Sansom3,4,* 1Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands 2Cancer Genomics Netherlands, Academic Medical Center, the Netherlands 3Cancer Research UK Beatson Institute, Glasgow, Scotland 4Institute of Cancer Sciences, University Of Glasgow, Glasgow, Scotland *Correspondence: [email protected] http://dx.doi.org/10.1016/j.devcel.2017.05.018
The intestinal crypt and its stem cells are dependent on the Wnt pathway. Reporting in Nature, Yan et al. (2017) show that Wnts and Wnt signaling potentiator R-spondins have non-interchangeable roles. Both are necessary for intestinal stem cell (ISC) maintenance, and R-spondins are the limiting factor that defines ISC number. The Wnt pathway is evolutionarily conserved, and Wnt ligands are a paradigm for morphogens in various model organisms. However, there is additional complexity in vertebrates in form of the R-spondin (Rspo)/Lgr axis that amplifies
the pathway and helps to fine-tune its activation (de Lau et al., 2012). Of all tissues, the intestinal epithelium is particularly reliant on the Wnt pathway. Wnt signaling is required for the maintenance of intestinal crypts. Specifically, the in-
456 Developmental Cell 41, June 5, 2017 ª 2017 Published by Elsevier Inc.
testinal stem cells and differentiated Paneth cells at the bottom of the crypt are characterized by high Wnt pathway activity. The discovery of the cell-surface marker Lgr5 on ISCs (Barker et al., 2007), and the ability to grow organoids
Previews Tregs Expand the Skin Stem Cell Niche Valerie Horsley1,* and Shruti Naik2 1Departments
of Molecular, Cellular and Developmental Biology and Dermatology, Yale University, New Haven, CT 06520, USA of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10065, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.devcel.2017.05.020 2Laboratory
Regulatory T cells (Tregs) are emerging as an essential stem cell niche component that promotes wound repair in adipose, muscle, and lung tissues. Recently in Cell, Ali et al. (2017) report that skin resident Tregs facilitate the proliferation and differentiation of hair follicle stem cells through Notch signaling. Hair follicle stem cells (HFSCs) reside in a specialized niche called the bulge and are essential for the cyclic regeneration of the hair follicle. Following hair follicle morphogenesis, the growing hair follicle ceases hair production and regresses (death phase, catagen), and only the stem cells in the bulge region of the follicle remain. The HFSCs remain dormant during the resting phase (telogen) of the hair cycle. When bulge stem cells become activated at the start of the next anagen, they exit the bulge niche, moving downward to produce highly proliferative progenitor cells at the base of the follicle in the hair germ (Zhang et al., 2009). The activation and physiology of HFSCs is tightly controlled by signals emanating from the dermis. By interacting directly or indirectly with the bulge at discrete phases of the hair follicle cycle, niche cells coordinate the cyclic generation and destruction of this tissue (Goldstein and Horsley, 2012; Hsu et al., 2014). For instance, the transition from quiescence to activation is dependent upon factors such as WNTs, fibroblast growth factors (FGFs), TGFb2, and PDGFa produced by the dermal papillae and adipocyte lineage, as well as neural and smooth muscle cells. A myriad of immune cells, including Foxp3+ regulatory T cells (Tregs), reside in close apposition to the hair follicle (Ali et. al 2017). Tregs are essential for counteracting inflammatory T cells, thus limiting immunopathology and promoting skin homeostasis. Despite their proximity and prevalence, the contribution of Tregs to HFSC activation was unknown. The paper from Ali et al. (2017) now shows that Tregs contribute to HFSC activation by promoting their proliferation and differentiation. An emerging role for Tregs beyond immune regulation has been reported in
more, genome-wide association studies have linked Tregs to hair follicle degeneration during alopecia areata (Petukhova et al., 2010). These studies have shed light on the repair function of Treg cells, and yet how these cells homeostatically maintain tissue integrity remains an open question. A recent study by Rosenblum and colleagues in Cell (Ali et al., 2017) has shed light on exactly how Tregs direct HFSC
the context of tissue repair (Arpaia et al., 2015; Burzyn et al., 2013). Tregs elaborate on the repertoire of tissue mediators to perform their non-canonical wound repair functions. For instance, lung and muscle Tregs express the EGFR ligand Amphiregulin to promote repair. Similarly, Tregs localize to the skin postnatally, where they have been shown to regulate wound healing (Nosbaum et al., 2016). Further-
Skin Anagen (active)
Telogen (quiescent) Inhibit Epidermal Fate
Notch activation
WNTS? BMP inhibitor FGF7/10 TGFβ2
Pro Dif liferat fere io ntia n tion
JAG1+ Treg α GF
PD
Upstream regulators of JAG1?
Hair Follicle Stem Cell JAG1positive Skin Treg JAG1negative Lymph Node Treg Adipocyte Precursor Cell Fibroblast Dermal Papillae
Lymph Node
Figure 1. JAG1+ Tregs-Induced HFSC Activation
Ali et al. (2017) report a role for JAG1+ skin regulatory T cells (Tregs) in promoting HFSC proliferation and differentiation via Notch signaling during the transition from telogen (quiescence) to anagen (activation).
Developmental Cell 41, June 5, 2017 ª 2017 Elsevier Inc. 455
Developmental Cell
Previews activation and, consequently, the HF cycle. The authors show that Tregs increase in the skin’s dermis prior to activation of hair follicle stem cells and localize adjacent to bulge stem cells. Importantly, ablation of Tregs completely abrogates the ability of the hair follicle to regenerate, implicating Tregs as a key component of the skin stem cell niche. Probing the molecular mechanism for this interaction, the authors compared mRNA expression of Tregs purified from the skin with Tregs isolated from lymph nodes to uncover the specific enrichment of the Notch ligand Jag1 in bulge-associated Tregs. Consistently, Notch target genes were reduced in HFSCs when Tregs were depleted. Beads coated with Jag1 were able to rescue the activation of the HFSCs in mice lacking Tregs, and conditional deletion of Jag1 from Tregs resulted in defects in activation of HFSCs. Together, these data highlight Tregsderived Jag1+ as a source of activating signals for HFSCs and add to our understanding of Notch signals in regulating HFSCs (Figure 1) (Blanpain et al., 2007). How Jag1 expression is regulated in Tregs and whether expression requires
T cell receptor engagement, interaction with HFSCs, and/or other niche components remains to be determined. Notch signaling underlies several aspects of cellular differentiation in interfollicular and follicular keratinocytes (Blanpain et al., 2007). How Treg-expressed Jag1 may contribute to regulation of these cells or other epidermal stem cells subsets, as well as their differentiated progeny, will be an intriguing future line of inquiry. Additionally, Notch signaling has been shown to have tumor-suppressive functions in the skin (Demehri et al., 2009), raising the possibility that Jag1 expression on Tregs contributes to tumor suppression. Jag1+ Tregs may thus promote tissue homeostasis by multiple mechanisms. Beyond the skin, it is tempting to speculate that Tregs similarly localize to and interact with stem cell niches in a range of tissues and via microenvironment-specific factors such as Jag1 to regulate the parenchyma at steady state.
Lowe, M.M., et al. (2017). Cell 169, 1119– 1129. Arpaia, N., Green, J.A., Moltedo, B., Arvey, A., Hemmers, S., Yuan, S., Treuting, P.M., and Rudensky, A.Y. (2015). Cell 162, 1078–1089. Blanpain, C., Horsley, V., and Fuchs, E. (2007). Cell 128, 445–458. Burzyn, D., Kuswanto, W., Kolodin, D., Shadrach, J.L., Cerletti, M., Jang, Y., Sefik, E., Tan, T.G., Wagers, A.J., Benoist, C., and Mathis, D. (2013). Cell 155, 1282–1295. Demehri, S., Turkoz, A., and Kopan, R. (2009). Cancer Cell 16, 55–66. Goldstein, J., and Horsley, V. (2012). Cell. Mol. Life Sci. 69, 2573–2582. Hsu, Y.C., Li, L., and Fuchs, E. (2014). Nat. Med. 20, 847–856. Nosbaum, A., Prevel, N., Truong, H.A., Mehta, P., Ettinger, M., Scharschmidt, T.C., Ali, N.H., Pauli, M.L., Abbas, A.K., and Rosenblum, M.D. (2016). J. Immunol. 196, 2010–2014. Petukhova, L., Duvic, M., Hordinsky, M., Norris, D., Price, V., Shimomura, Y., Kim, H., Singh, P., Lee, A., Chen, W.V., et al. (2010). Nature 466, 113–117.
REFERENCES Ali, N., Zirak, B., Rodriguez, R.S., Pauli, M.L., Truong, H.-A., Lai, K., Ahn, R., Corbin, K.,
Zhang, Y.V., Cheong, J., Ciapurin, N., McDermitt, D.J., and Tumbar, T. (2009). Cell Stem Cell 5, 267–278.
R-spondin Is More Than Just Wnt’s Sidekick David J. Huels1,2 and Owen J. Sansom3,4,* 1Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands 2Cancer Genomics Netherlands, Academic Medical Center, the Netherlands 3Cancer Research UK Beatson Institute, Glasgow, Scotland 4Institute of Cancer Sciences, University Of Glasgow, Glasgow, Scotland *Correspondence: [email protected] http://dx.doi.org/10.1016/j.devcel.2017.05.018
The intestinal crypt and its stem cells are dependent on the Wnt pathway. Reporting in Nature, Yan et al. (2017) show that Wnts and Wnt signaling potentiator R-spondins have non-interchangeable roles. Both are necessary for intestinal stem cell (ISC) maintenance, and R-spondins are the limiting factor that defines ISC number. The Wnt pathway is evolutionarily conserved, and Wnt ligands are a paradigm for morphogens in various model organisms. However, there is additional complexity in vertebrates in form of the R-spondin (Rspo)/Lgr axis that amplifies
the pathway and helps to fine-tune its activation (de Lau et al., 2012). Of all tissues, the intestinal epithelium is particularly reliant on the Wnt pathway. Wnt signaling is required for the maintenance of intestinal crypts. Specifically, the in-
456 Developmental Cell 41, June 5, 2017 ª 2017 Published by Elsevier Inc.
testinal stem cells and differentiated Paneth cells at the bottom of the crypt are characterized by high Wnt pathway activity. The discovery of the cell-surface marker Lgr5 on ISCs (Barker et al., 2007), and the ability to grow organoids