Letter | Published:

Parent stem cells can serve as niches for their daughter cells

Nature volume 523, pages 597601 (30 July 2015) | Download Citation

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Abstract

Stem cells integrate inputs from multiple sources. Stem cell niches provide signals that promote stem cell maintenance1,2, while differentiated daughter cells are known to provide feedback signals to regulate stem cell replication and differentiation3,4,5,6. Recently, stem cells have been shown to regulate themselves using an autocrine mechanism7. The existence of a ‘stem cell niche’ was first postulated by Schofield in 1978 to define local environments necessary for the maintenance of haematopoietic stem cells1. Since then, an increasing body of work has focused on defining stem cell niches1,2,3,4,5,6. Yet little is known about how progenitor cell and differentiated cell numbers and proportions are maintained. In the airway epithelium, basal cells function as stem/progenitor cells that can both self-renew and produce differentiated secretory cells and ciliated cells8,9. Secretory cells also act as transit-amplifying cells that eventually differentiate into post-mitotic ciliated cells9,10 . Here we describe a mode of cell regulation in which adult mammalian stem/progenitor cells relay a forward signal to their own progeny. Surprisingly, this forward signal is shown to be necessary for daughter cell maintenance. Using a combination of cell ablation, lineage tracing and signalling pathway modulation, we show that airway basal stem/progenitor cells continuously supply a Notch ligand to their daughter secretory cells. Without these forward signals, the secretory progenitor cell pool fails to be maintained and secretory cells execute a terminal differentiation program and convert into ciliated cells. Thus, a parent stem/progenitor cell can serve as a functional daughter cell niche.

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Acknowledgements

We thank A. Glick for providing the CK5rtTA mice, B. Hogan for providing CK5creER and SCGB1A1creER mice and Y.-Y. Kong for sharing the Mib1 floxed mice. B. Z. Stanger provided the RBPjk floxed mice and shared protocols for the immunohistochemical detection of Notch components. We also thank B. Stripp for providing the goat anti-SCGB1A1 antibody. We wish to extend our thanks to all of the members of the Rajagopal laboratory and the HSCI flow cytometry core facility. This research was supported by the New York Stem Cell Foundation (J.R. is a New York Stem Cell Foundation-Robertson Investigator), by a National Institutes of Health-National Heart, Lung, and Blood Institute Early Career Research New Faculty (P30) award (5P30HL101287-02), an RO1 (RO1HL118185) from NIH-NHLBI (to J.R.) and a Harvard Stem Cell Institute (HSCI) Junior Investigator Grant (to J.R.). J.R. is also the Maroni Research Scholar at Massachusetts General Hospital.

Author information

Author notes

    • Ana Pardo-Saganta
    •  & Purushothama Rao Tata

    These authors contributed equally to this work.

Affiliations

  1. Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA

    • Ana Pardo-Saganta
    • , Purushothama Rao Tata
    • , Brandon M. Law
    • , Borja Saez
    • , Ryan Dz-Wei Chow
    • , Mythili Prabhu
    •  & Jayaraj Rajagopal
  2. Departments of Internal Medicine and Pediatrics, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA

    • Ana Pardo-Saganta
    • , Purushothama Rao Tata
    • , Brandon M. Law
    • , Ryan Dz-Wei Chow
    • , Mythili Prabhu
    •  & Jayaraj Rajagopal
  3. Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA

    • Ana Pardo-Saganta
    • , Purushothama Rao Tata
    • , Brandon M. Law
    • , Borja Saez
    • , Ryan Dz-Wei Chow
    • , Mythili Prabhu
    •  & Jayaraj Rajagopal
  4. Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, Massachusetts 02138, USA

    • Borja Saez
  5. Center for Molecular Medicine, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, Maine 04074, USA

    • Thomas Gridley

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Contributions

A.P.-S. designed and performed the experiments and co-wrote the manuscript; P.R.T. performed the ablation experiments and edited the manuscript; B.M.L. optimized the immunodetection of N2ICD, analysed the phenotype of RBPjk and Mib1 deletion in vivo and co-wrote the manuscript; B.S. performed flow cytometry experiments and analysis, contributed to the in vitro experiments and edited the manuscript; R.D.-W.C. and M.P. helped with the analysis of the in vivo experiments; T.G. contributed to Jag2 deletion in vivo experiments; J.R. suggested and co-designed the study and co-wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jayaraj Rajagopal.

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DOI

https://doi.org/10.1038/nature14553

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