Apoptotic cells represent a dynamic stem cell niche governing proliferation and tissue regeneration

Roi Ankawa; Nitzan Goldberger; Yahav Yosefzon; Elle Koren; Marianna Yusupova; Daniel Rosner; Alona Feldman; Shulamit Baror-Sebban; Yosef Buganim; David J. Simon; Marc Tessier-Lavigne; Yaron Fuchs

doi:10.1016/j.devcel.2021.06.008

Apoptotic cells represent a dynamic stem cell niche governing proliferation and tissue regeneration

Roi Ankawa, Nitzan Goldberger, Yahav Yosefzon, Elle Koren, Marianna Yusupova, Daniel Rosner, Alona Feldman, Shulamit Baror-Sebban, Yosef Buganim, David J. Simon, Marc Tessier-Lavigne, Yaron Fuchs^*

^*Corresponding author for this work

Department of Developmental Biology and Cancer Research

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

Abstract

Stem cells (SCs) play a key role in homeostasis and repair. While many studies have focused on SC self-renewal and differentiation, little is known regarding the molecular mechanism regulating SC elimination and compensation upon loss. Here, we report that Caspase-9 deletion in hair follicle SCs (HFSCs) attenuates the apoptotic cascade, resulting in significant temporal delays. Surprisingly, Casp9-deficient HFSCs accumulate high levels of cleaved caspase-3 and are improperly cleared due to an essential caspase-3/caspase-9 feedforward loop. These SCs are retained in an apoptotic-engaged state, serving as mitogenic signaling centers by continuously releasing Wnt3 and instructing proliferation. Investigating the underlying mechanism, we reveal a caspase-3/Dusp8/p38 module responsible for Wnt3 induction, which operates in both normal and Casp9-deleted HFSCs. Notably, Casp9-deleted mice display accelerated wound repair and de novo hair follicle regeneration.

Original language	American English
Pages (from-to)	1900-1916.e5
Journal	Developmental Cell
Volume	56
Issue number	13
DOIs	https://doi.org/10.1016/j.devcel.2021.06.008
State	Published - 12 Jul 2021

Bibliographical note

Funding Information:
We apologize to colleagues whose contributions could not be cited due to space constraints. We would like to thank: Fuchs lab members, G. Ventura, L. Voslovizer, X. Velasquez, and I. Maniv. We thank V. Zlobin at the Technion PCRA and E. Barak for flow cytometry. Figure 5 L and graphical abstract were generated using BioRender. Work in M.T.L. laboratory was supported by NIH grant R01NS089786 . Y.F. was supported by the EMBO Young Investigator program, ICRF ( 15-771-RCDA ) grants, ISF individual 2124/19 and IPMP 1019045-2029637 grants, and ICRF acceleration AG-17-917 .

Funding Information:
We apologize to colleagues whose contributions could not be cited due to space constraints. We would like to thank: Fuchs lab members, G. Ventura, L. Voslovizer, X. Velasquez, and I. Maniv. We thank V. Zlobin at the Technion PCRA and E. Barak for flow cytometry. Figure 5L and graphical abstract were generated using BioRender. Work in M.T.L. laboratory was supported by NIH grant R01NS089786. Y.F. was supported by the EMBO Young Investigator program, ICRF (15-771-RCDA) grants, ISF individual 2124/19 and IPMP 1019045-2029637 grants, and ICRF acceleration AG-17-917. R.A. N.G. Y.Y. E.K. S.B.S. Y.B. and Y.F. designed and performed experiments. M.Y. performed RNA-seq analysis. D.R. and A.F. provided technical assistance with experiments and data analyses. D.J.S. and M.T.L. designed and created the Casp9fl/f mouse. R.A. E.K. and Y.F. wrote the manuscript. M.T.-L. is a director of Denali Therapeutics and Regeneron Pharmaceuticals. Other authors declare no competing interests.

Publisher Copyright:
© 2021 Elsevier Inc.

Keywords

Wnt3
apoptosis
caspase
hair follicle
regeneration
stem cells
wound repair

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10.1016/j.devcel.2021.06.008

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@article{aeaed42a91624c57af20e889c2741767,

title = "Apoptotic cells represent a dynamic stem cell niche governing proliferation and tissue regeneration",

abstract = "Stem cells (SCs) play a key role in homeostasis and repair. While many studies have focused on SC self-renewal and differentiation, little is known regarding the molecular mechanism regulating SC elimination and compensation upon loss. Here, we report that Caspase-9 deletion in hair follicle SCs (HFSCs) attenuates the apoptotic cascade, resulting in significant temporal delays. Surprisingly, Casp9-deficient HFSCs accumulate high levels of cleaved caspase-3 and are improperly cleared due to an essential caspase-3/caspase-9 feedforward loop. These SCs are retained in an apoptotic-engaged state, serving as mitogenic signaling centers by continuously releasing Wnt3 and instructing proliferation. Investigating the underlying mechanism, we reveal a caspase-3/Dusp8/p38 module responsible for Wnt3 induction, which operates in both normal and Casp9-deleted HFSCs. Notably, Casp9-deleted mice display accelerated wound repair and de novo hair follicle regeneration.",

keywords = "Wnt3, apoptosis, caspase, hair follicle, regeneration, stem cells, wound repair",

author = "Roi Ankawa and Nitzan Goldberger and Yahav Yosefzon and Elle Koren and Marianna Yusupova and Daniel Rosner and Alona Feldman and Shulamit Baror-Sebban and Yosef Buganim and Simon, {David J.} and Marc Tessier-Lavigne and Yaron Fuchs",

note = "Funding Information: We apologize to colleagues whose contributions could not be cited due to space constraints. We would like to thank: Fuchs lab members, G. Ventura, L. Voslovizer, X. Velasquez, and I. Maniv. We thank V. Zlobin at the Technion PCRA and E. Barak for flow cytometry. Figure 5 L and graphical abstract were generated using BioRender. Work in M.T.L. laboratory was supported by NIH grant R01NS089786 . Y.F. was supported by the EMBO Young Investigator program, ICRF ( 15-771-RCDA ) grants, ISF individual 2124/19 and IPMP 1019045-2029637 grants, and ICRF acceleration AG-17-917 . Funding Information: We apologize to colleagues whose contributions could not be cited due to space constraints. We would like to thank: Fuchs lab members, G. Ventura, L. Voslovizer, X. Velasquez, and I. Maniv. We thank V. Zlobin at the Technion PCRA and E. Barak for flow cytometry. Figure 5L and graphical abstract were generated using BioRender. Work in M.T.L. laboratory was supported by NIH grant R01NS089786. Y.F. was supported by the EMBO Young Investigator program, ICRF (15-771-RCDA) grants, ISF individual 2124/19 and IPMP 1019045-2029637 grants, and ICRF acceleration AG-17-917. R.A. N.G. Y.Y. E.K. S.B.S. Y.B. and Y.F. designed and performed experiments. M.Y. performed RNA-seq analysis. D.R. and A.F. provided technical assistance with experiments and data analyses. D.J.S. and M.T.L. designed and created the Casp9fl/f mouse. R.A. E.K. and Y.F. wrote the manuscript. M.T.-L. is a director of Denali Therapeutics and Regeneron Pharmaceuticals. Other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

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doi = "10.1016/j.devcel.2021.06.008",

language = "American English",

volume = "56",

pages = "1900--1916.e5",

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T1 - Apoptotic cells represent a dynamic stem cell niche governing proliferation and tissue regeneration

AU - Ankawa, Roi

AU - Goldberger, Nitzan

AU - Yosefzon, Yahav

AU - Koren, Elle

AU - Yusupova, Marianna

AU - Rosner, Daniel

AU - Feldman, Alona

AU - Baror-Sebban, Shulamit

AU - Buganim, Yosef

AU - Simon, David J.

AU - Tessier-Lavigne, Marc

AU - Fuchs, Yaron

N1 - Funding Information: We apologize to colleagues whose contributions could not be cited due to space constraints. We would like to thank: Fuchs lab members, G. Ventura, L. Voslovizer, X. Velasquez, and I. Maniv. We thank V. Zlobin at the Technion PCRA and E. Barak for flow cytometry. Figure 5 L and graphical abstract were generated using BioRender. Work in M.T.L. laboratory was supported by NIH grant R01NS089786 . Y.F. was supported by the EMBO Young Investigator program, ICRF ( 15-771-RCDA ) grants, ISF individual 2124/19 and IPMP 1019045-2029637 grants, and ICRF acceleration AG-17-917 . Funding Information: We apologize to colleagues whose contributions could not be cited due to space constraints. We would like to thank: Fuchs lab members, G. Ventura, L. Voslovizer, X. Velasquez, and I. Maniv. We thank V. Zlobin at the Technion PCRA and E. Barak for flow cytometry. Figure 5L and graphical abstract were generated using BioRender. Work in M.T.L. laboratory was supported by NIH grant R01NS089786. Y.F. was supported by the EMBO Young Investigator program, ICRF (15-771-RCDA) grants, ISF individual 2124/19 and IPMP 1019045-2029637 grants, and ICRF acceleration AG-17-917. R.A. N.G. Y.Y. E.K. S.B.S. Y.B. and Y.F. designed and performed experiments. M.Y. performed RNA-seq analysis. D.R. and A.F. provided technical assistance with experiments and data analyses. D.J.S. and M.T.L. designed and created the Casp9fl/f mouse. R.A. E.K. and Y.F. wrote the manuscript. M.T.-L. is a director of Denali Therapeutics and Regeneron Pharmaceuticals. Other authors declare no competing interests. Publisher Copyright: © 2021 Elsevier Inc.

PY - 2021/7/12

Y1 - 2021/7/12

N2 - Stem cells (SCs) play a key role in homeostasis and repair. While many studies have focused on SC self-renewal and differentiation, little is known regarding the molecular mechanism regulating SC elimination and compensation upon loss. Here, we report that Caspase-9 deletion in hair follicle SCs (HFSCs) attenuates the apoptotic cascade, resulting in significant temporal delays. Surprisingly, Casp9-deficient HFSCs accumulate high levels of cleaved caspase-3 and are improperly cleared due to an essential caspase-3/caspase-9 feedforward loop. These SCs are retained in an apoptotic-engaged state, serving as mitogenic signaling centers by continuously releasing Wnt3 and instructing proliferation. Investigating the underlying mechanism, we reveal a caspase-3/Dusp8/p38 module responsible for Wnt3 induction, which operates in both normal and Casp9-deleted HFSCs. Notably, Casp9-deleted mice display accelerated wound repair and de novo hair follicle regeneration.

AB - Stem cells (SCs) play a key role in homeostasis and repair. While many studies have focused on SC self-renewal and differentiation, little is known regarding the molecular mechanism regulating SC elimination and compensation upon loss. Here, we report that Caspase-9 deletion in hair follicle SCs (HFSCs) attenuates the apoptotic cascade, resulting in significant temporal delays. Surprisingly, Casp9-deficient HFSCs accumulate high levels of cleaved caspase-3 and are improperly cleared due to an essential caspase-3/caspase-9 feedforward loop. These SCs are retained in an apoptotic-engaged state, serving as mitogenic signaling centers by continuously releasing Wnt3 and instructing proliferation. Investigating the underlying mechanism, we reveal a caspase-3/Dusp8/p38 module responsible for Wnt3 induction, which operates in both normal and Casp9-deleted HFSCs. Notably, Casp9-deleted mice display accelerated wound repair and de novo hair follicle regeneration.

KW - Wnt3

KW - apoptosis

KW - caspase

KW - hair follicle

KW - regeneration

KW - stem cells

KW - wound repair

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U2 - 10.1016/j.devcel.2021.06.008

DO - 10.1016/j.devcel.2021.06.008

M3 - Article

C2 - 34197726

AN - SCOPUS:85109448414

SN - 1534-5807

VL - 56

SP - 1900-1916.e5

JO - Developmental Cell

JF - Developmental Cell

IS - 13

ER -

Apoptotic cells represent a dynamic stem cell niche governing proliferation and tissue regeneration

Abstract

Bibliographical note

Keywords

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