A Cellular Taxonomy of the Bone Marrow Stroma in Homeostasis and Leukemia

Ninib Baryawno; Dariusz Przybylski; Monika S. Kowalczyk; Youmna Kfoury; Nicolas Severe; Karin Gustafsson; Konstantinos D. Kokkaliaris; Francois Mercier; Marcin Tabaka; Matan Hofree; Danielle Dionne; Ani Papazian; Dongjun Lee; Orr Ashenberg; Ayshwarya Subramanian; Eeshit Dhaval Vaishnav; Orit Rozenblatt-Rosen; Aviv Regev; David T. Scadden

doi:10.1016/j.cell.2019.04.040

A Cellular Taxonomy of the Bone Marrow Stroma in Homeostasis and Leukemia

Ninib Baryawno, Dariusz Przybylski, Monika S. Kowalczyk, Youmna Kfoury, Nicolas Severe, Karin Gustafsson, Konstantinos D. Kokkaliaris, Francois Mercier, Marcin Tabaka, Matan Hofree, Danielle Dionne, Ani Papazian, Dongjun Lee, Orr Ashenberg, Ayshwarya Subramanian, Eeshit Dhaval Vaishnav, Orit Rozenblatt-Rosen, Aviv Regev^*, David T. Scadden

^*Corresponding author for this work

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

450 Scopus citations

Abstract

Stroma is a poorly defined non-parenchymal component of virtually every organ with key roles in organ development, homeostasis, and repair. Studies of the bone marrow stroma have defined individual populations in the stem cell niche regulating hematopoietic regeneration and capable of initiating leukemia. Here, we use single-cell RNA sequencing (scRNA-seq) to define a cellular taxonomy of the mouse bone marrow stroma and its perturbation by malignancy. We identified seventeen stromal subsets expressing distinct hematopoietic regulatory genes spanning new fibroblastic and osteoblastic subpopulations including distinct osteoblast differentiation trajectories. Emerging acute myeloid leukemia impaired mesenchymal osteogenic differentiation and reduced regulatory molecules necessary for normal hematopoiesis. These data suggest that tissue stroma responds to malignant cells by disadvantaging normal parenchymal cells. Our taxonomy of the stromal compartment provides a comprehensive bone marrow cell census and experimental support for cancer cell crosstalk with specific stromal elements to impair normal tissue function and thereby enable emergent cancer.

Original language	American English
Pages (from-to)	1915-1932.e16
Journal	Cell
Volume	177
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2019.04.040
State	Published - 13 Jun 2019
Externally published	Yes

Bibliographical note

Funding Information:
We thank Professor Henry Kronenberg for helpful comments, Leslie Gaffney and Anna Hupalowska for helping with figures, and Carl de Boer, Christopher Smillie, Adam Haber, Joshua Gould, and Bo Li for additional help. N.B. was funded by the Swedish Research Council and The Childhood Cancer Foundation in Sweden. M.S.K. was supported by Charles A. King Trust Postdoctoral Research Fellowship Program and the Simeon J. Fortin Charitable Foundation . Work was supported by the Klarman Cell Observatory and HHMI (to A.R.), NIH ( DK107784 ), and the Gerald and Darlene Jordan Professorship (to D.T.S.).

Funding Information:
We thank Professor Henry Kronenberg for helpful comments, Leslie Gaffney and Anna Hupalowska for helping with figures, and Carl de Boer, Christopher Smillie, Adam Haber, Joshua Gould, and Bo Li for additional help. N.B. was funded by the Swedish Research Council and The Childhood Cancer Foundation in Sweden. M.S.K. was supported by Charles A. King Trust Postdoctoral Research Fellowship Program and the Simeon J. Fortin Charitable Foundation. Work was supported by the Klarman Cell Observatory and HHMI (to A.R.), NIH (DK107784), and the Gerald and Darlene Jordan Professorship (to D.T.S.). Conceptualization, N.B. D.P. M.S.K. A.R. and D.T.S; Investigation, N.B. M.S.K. N.S. K.G. A.P. F.M. D.D. K.D.K. M.H. D.D. O.R.-R. and D.L; Validation, N.B. and K.D.K.; Computational Investigation and Analysis, D.P. with help and code contributions from M.T. M.H. A.S. O.A. and E.D.V.; Writing – Original Draft, N.B. D.P. M.K. A.R. and D.T.S.; Writing – Review & Editing, N.B. D.P. M.K. Y.K. N.S. K.D.K. A.R. and D.T.S; Funding Acquisition, Resources, & Supervision, A.R. and D.T.S. D.T.S. is a director and shareholder of Magenta Therapeutics, Agios Pharmaceuticals, Editas Medicines, Clear Creek Bio, Red Oak Medicines, and LifeVaultBio, a shareholder of Fate Therapeutics, a consultant for Magenta Therapeutics, Clear Creek Bio, Red Oak Medicines, and VCanBio, and a SAB member of FOG Pharma. A.R. is a founder and equity holder of Celsius Therapeutics and a member of the SAB for ThermoFisher Scientific and Syros Pharmaceuticals. M.S.K. is employed by Celsius Therapeutics. The authors have filed for a patent (62/808,177).

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

bone marrow niche
hematopoiesis
leukemia
single-cell RNA-sequencing
stem cell
stroma
tumor microenvironment

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cell.2019.04.040

Cite this

Baryawno, N., Przybylski, D., Kowalczyk, M. S., Kfoury, Y., Severe, N., Gustafsson, K., Kokkaliaris, K. D., Mercier, F., Tabaka, M., Hofree, M., Dionne, D., Papazian, A., Lee, D., Ashenberg, O., Subramanian, A., Vaishnav, E. D., Rozenblatt-Rosen, O., Regev, A., & Scadden, D. T. (2019). A Cellular Taxonomy of the Bone Marrow Stroma in Homeostasis and Leukemia. Cell, 177(7), 1915-1932.e16. https://doi.org/10.1016/j.cell.2019.04.040

@article{fd20091bdb9643958b887af13dc39560,

title = "A Cellular Taxonomy of the Bone Marrow Stroma in Homeostasis and Leukemia",

abstract = "Stroma is a poorly defined non-parenchymal component of virtually every organ with key roles in organ development, homeostasis, and repair. Studies of the bone marrow stroma have defined individual populations in the stem cell niche regulating hematopoietic regeneration and capable of initiating leukemia. Here, we use single-cell RNA sequencing (scRNA-seq) to define a cellular taxonomy of the mouse bone marrow stroma and its perturbation by malignancy. We identified seventeen stromal subsets expressing distinct hematopoietic regulatory genes spanning new fibroblastic and osteoblastic subpopulations including distinct osteoblast differentiation trajectories. Emerging acute myeloid leukemia impaired mesenchymal osteogenic differentiation and reduced regulatory molecules necessary for normal hematopoiesis. These data suggest that tissue stroma responds to malignant cells by disadvantaging normal parenchymal cells. Our taxonomy of the stromal compartment provides a comprehensive bone marrow cell census and experimental support for cancer cell crosstalk with specific stromal elements to impair normal tissue function and thereby enable emergent cancer.",

keywords = "bone marrow niche, hematopoiesis, leukemia, single-cell RNA-sequencing, stem cell, stroma, tumor microenvironment",

author = "Ninib Baryawno and Dariusz Przybylski and Kowalczyk, {Monika S.} and Youmna Kfoury and Nicolas Severe and Karin Gustafsson and Kokkaliaris, {Konstantinos D.} and Francois Mercier and Marcin Tabaka and Matan Hofree and Danielle Dionne and Ani Papazian and Dongjun Lee and Orr Ashenberg and Ayshwarya Subramanian and Vaishnav, {Eeshit Dhaval} and Orit Rozenblatt-Rosen and Aviv Regev and Scadden, {David T.}",

note = "Funding Information: We thank Professor Henry Kronenberg for helpful comments, Leslie Gaffney and Anna Hupalowska for helping with figures, and Carl de Boer, Christopher Smillie, Adam Haber, Joshua Gould, and Bo Li for additional help. N.B. was funded by the Swedish Research Council and The Childhood Cancer Foundation in Sweden. M.S.K. was supported by Charles A. King Trust Postdoctoral Research Fellowship Program and the Simeon J. Fortin Charitable Foundation . Work was supported by the Klarman Cell Observatory and HHMI (to A.R.), NIH ( DK107784 ), and the Gerald and Darlene Jordan Professorship (to D.T.S.). Funding Information: We thank Professor Henry Kronenberg for helpful comments, Leslie Gaffney and Anna Hupalowska for helping with figures, and Carl de Boer, Christopher Smillie, Adam Haber, Joshua Gould, and Bo Li for additional help. N.B. was funded by the Swedish Research Council and The Childhood Cancer Foundation in Sweden. M.S.K. was supported by Charles A. King Trust Postdoctoral Research Fellowship Program and the Simeon J. Fortin Charitable Foundation. Work was supported by the Klarman Cell Observatory and HHMI (to A.R.), NIH (DK107784), and the Gerald and Darlene Jordan Professorship (to D.T.S.). Conceptualization, N.B. D.P. M.S.K. A.R. and D.T.S; Investigation, N.B. M.S.K. N.S. K.G. A.P. F.M. D.D. K.D.K. M.H. D.D. O.R.-R. and D.L; Validation, N.B. and K.D.K.; Computational Investigation and Analysis, D.P. with help and code contributions from M.T. M.H. A.S. O.A. and E.D.V.; Writing – Original Draft, N.B. D.P. M.K. A.R. and D.T.S.; Writing – Review & Editing, N.B. D.P. M.K. Y.K. N.S. K.D.K. A.R. and D.T.S; Funding Acquisition, Resources, & Supervision, A.R. and D.T.S. D.T.S. is a director and shareholder of Magenta Therapeutics, Agios Pharmaceuticals, Editas Medicines, Clear Creek Bio, Red Oak Medicines, and LifeVaultBio, a shareholder of Fate Therapeutics, a consultant for Magenta Therapeutics, Clear Creek Bio, Red Oak Medicines, and VCanBio, and a SAB member of FOG Pharma. A.R. is a founder and equity holder of Celsius Therapeutics and a member of the SAB for ThermoFisher Scientific and Syros Pharmaceuticals. M.S.K. is employed by Celsius Therapeutics. The authors have filed for a patent (62/808,177). Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = jun,

day = "13",

doi = "10.1016/j.cell.2019.04.040",

language = "American English",

volume = "177",

pages = "1915--1932.e16",

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Baryawno, N, Przybylski, D, Kowalczyk, MS, Kfoury, Y, Severe, N, Gustafsson, K, Kokkaliaris, KD, Mercier, F, Tabaka, M, Hofree, M, Dionne, D, Papazian, A, Lee, D, Ashenberg, O, Subramanian, A, Vaishnav, ED, Rozenblatt-Rosen, O, Regev, A & Scadden, DT 2019, 'A Cellular Taxonomy of the Bone Marrow Stroma in Homeostasis and Leukemia', Cell, vol. 177, no. 7, pp. 1915-1932.e16. https://doi.org/10.1016/j.cell.2019.04.040

TY - JOUR

T1 - A Cellular Taxonomy of the Bone Marrow Stroma in Homeostasis and Leukemia

AU - Baryawno, Ninib

AU - Przybylski, Dariusz

AU - Kowalczyk, Monika S.

AU - Kfoury, Youmna

AU - Severe, Nicolas

AU - Gustafsson, Karin

AU - Kokkaliaris, Konstantinos D.

AU - Mercier, Francois

AU - Tabaka, Marcin

AU - Hofree, Matan

AU - Dionne, Danielle

AU - Papazian, Ani

AU - Lee, Dongjun

AU - Ashenberg, Orr

AU - Subramanian, Ayshwarya

AU - Vaishnav, Eeshit Dhaval

AU - Rozenblatt-Rosen, Orit

AU - Regev, Aviv

AU - Scadden, David T.

N1 - Funding Information: We thank Professor Henry Kronenberg for helpful comments, Leslie Gaffney and Anna Hupalowska for helping with figures, and Carl de Boer, Christopher Smillie, Adam Haber, Joshua Gould, and Bo Li for additional help. N.B. was funded by the Swedish Research Council and The Childhood Cancer Foundation in Sweden. M.S.K. was supported by Charles A. King Trust Postdoctoral Research Fellowship Program and the Simeon J. Fortin Charitable Foundation . Work was supported by the Klarman Cell Observatory and HHMI (to A.R.), NIH ( DK107784 ), and the Gerald and Darlene Jordan Professorship (to D.T.S.). Funding Information: We thank Professor Henry Kronenberg for helpful comments, Leslie Gaffney and Anna Hupalowska for helping with figures, and Carl de Boer, Christopher Smillie, Adam Haber, Joshua Gould, and Bo Li for additional help. N.B. was funded by the Swedish Research Council and The Childhood Cancer Foundation in Sweden. M.S.K. was supported by Charles A. King Trust Postdoctoral Research Fellowship Program and the Simeon J. Fortin Charitable Foundation. Work was supported by the Klarman Cell Observatory and HHMI (to A.R.), NIH (DK107784), and the Gerald and Darlene Jordan Professorship (to D.T.S.). Conceptualization, N.B. D.P. M.S.K. A.R. and D.T.S; Investigation, N.B. M.S.K. N.S. K.G. A.P. F.M. D.D. K.D.K. M.H. D.D. O.R.-R. and D.L; Validation, N.B. and K.D.K.; Computational Investigation and Analysis, D.P. with help and code contributions from M.T. M.H. A.S. O.A. and E.D.V.; Writing – Original Draft, N.B. D.P. M.K. A.R. and D.T.S.; Writing – Review & Editing, N.B. D.P. M.K. Y.K. N.S. K.D.K. A.R. and D.T.S; Funding Acquisition, Resources, & Supervision, A.R. and D.T.S. D.T.S. is a director and shareholder of Magenta Therapeutics, Agios Pharmaceuticals, Editas Medicines, Clear Creek Bio, Red Oak Medicines, and LifeVaultBio, a shareholder of Fate Therapeutics, a consultant for Magenta Therapeutics, Clear Creek Bio, Red Oak Medicines, and VCanBio, and a SAB member of FOG Pharma. A.R. is a founder and equity holder of Celsius Therapeutics and a member of the SAB for ThermoFisher Scientific and Syros Pharmaceuticals. M.S.K. is employed by Celsius Therapeutics. The authors have filed for a patent (62/808,177). Publisher Copyright: © 2019 Elsevier Inc.

PY - 2019/6/13

Y1 - 2019/6/13

N2 - Stroma is a poorly defined non-parenchymal component of virtually every organ with key roles in organ development, homeostasis, and repair. Studies of the bone marrow stroma have defined individual populations in the stem cell niche regulating hematopoietic regeneration and capable of initiating leukemia. Here, we use single-cell RNA sequencing (scRNA-seq) to define a cellular taxonomy of the mouse bone marrow stroma and its perturbation by malignancy. We identified seventeen stromal subsets expressing distinct hematopoietic regulatory genes spanning new fibroblastic and osteoblastic subpopulations including distinct osteoblast differentiation trajectories. Emerging acute myeloid leukemia impaired mesenchymal osteogenic differentiation and reduced regulatory molecules necessary for normal hematopoiesis. These data suggest that tissue stroma responds to malignant cells by disadvantaging normal parenchymal cells. Our taxonomy of the stromal compartment provides a comprehensive bone marrow cell census and experimental support for cancer cell crosstalk with specific stromal elements to impair normal tissue function and thereby enable emergent cancer.

AB - Stroma is a poorly defined non-parenchymal component of virtually every organ with key roles in organ development, homeostasis, and repair. Studies of the bone marrow stroma have defined individual populations in the stem cell niche regulating hematopoietic regeneration and capable of initiating leukemia. Here, we use single-cell RNA sequencing (scRNA-seq) to define a cellular taxonomy of the mouse bone marrow stroma and its perturbation by malignancy. We identified seventeen stromal subsets expressing distinct hematopoietic regulatory genes spanning new fibroblastic and osteoblastic subpopulations including distinct osteoblast differentiation trajectories. Emerging acute myeloid leukemia impaired mesenchymal osteogenic differentiation and reduced regulatory molecules necessary for normal hematopoiesis. These data suggest that tissue stroma responds to malignant cells by disadvantaging normal parenchymal cells. Our taxonomy of the stromal compartment provides a comprehensive bone marrow cell census and experimental support for cancer cell crosstalk with specific stromal elements to impair normal tissue function and thereby enable emergent cancer.

KW - bone marrow niche

KW - hematopoiesis

KW - leukemia

KW - single-cell RNA-sequencing

KW - stem cell

KW - stroma

KW - tumor microenvironment

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U2 - 10.1016/j.cell.2019.04.040

DO - 10.1016/j.cell.2019.04.040

M3 - Article

C2 - 31130381

AN - SCOPUS:85066308329

SN - 0092-8674

VL - 177

SP - 1915-1932.e16

JO - Cell

JF - Cell

IS - 7

ER -

A Cellular Taxonomy of the Bone Marrow Stroma in Homeostasis and Leukemia

Abstract

Bibliographical note

Keywords

UN SDGs

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