Endothelium-derived stromal cells contribute to hematopoietic bone marrow niche formation

Keane Jared Guillaume Kenswil; Paola Pisterzi; Gonzalo Sánchez-Duffhues; Claire van Dijk; Andrea Lolli; Callie Knuth; Byambasuren Vanchin; Adrian Christopher Jaramillo; Remco Michiel Hoogenboezem; Mathijs Arnoud Sanders; Jacqueline Feyen; Tom Cupedo; Ivan G. Costa; Ronghui Li; Eric Moniqué Johannes Bindels; Kirsten Lodder; Bianca Blom; Pieter Koen Bos; Marie José Goumans; Peter ten Dijke; Eric Farrell; Guido Krenning; Marc Hermanus Gerardus Petrus Raaijmakers

doi:10.1016/j.stem.2021.01.006

Endothelium-derived stromal cells contribute to hematopoietic bone marrow niche formation

Keane Jared Guillaume Kenswil, Paola Pisterzi, Gonzalo Sánchez-Duffhues, Claire van Dijk, Andrea Lolli, Callie Knuth, Byambasuren Vanchin, Adrian Christopher Jaramillo, Remco Michiel Hoogenboezem, Mathijs Arnoud Sanders, Jacqueline Feyen, Tom Cupedo, Ivan G. Costa, Ronghui Li, Eric Moniqué Johannes Bindels, Kirsten Lodder, Bianca Blom, Pieter Koen Bos, Marie José Goumans, Peter ten DijkeEric Farrell, Guido Krenning, Marc Hermanus Gerardus Petrus Raaijmakers^*

^*Corresponding author for this work

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Abstract

Bone marrow stromal cells (BMSCs) play pivotal roles in tissue maintenance and regeneration. Their origins, however, remain incompletely understood. Here we identify rare LNGFR⁺ cells in human fetal and regenerative bone marrow that co-express endothelial and stromal markers. This endothelial subpopulation displays transcriptional reprogramming consistent with endothelial-to-mesenchymal transition (EndoMT) and can generate multipotent stromal cells that reconstitute the bone marrow (BM) niche upon transplantation. Single-cell transcriptomics and lineage tracing in mice confirm robust and sustained contributions of EndoMT to bone precursor and hematopoietic niche pools. Interleukin-33 (IL-33) is overexpressed in subsets of EndoMT cells and drives this conversion process through ST2 receptor signaling. These data reveal generation of tissue-forming BMSCs from mouse and human endothelial cells and may be instructive for approaches to human tissue regeneration.

Original language	English
Pages (from-to)	653-670.e11
Journal	Cell Stem Cell
Volume	28
Issue number	4
DOIs	https://doi.org/10.1016/j.stem.2021.01.006
Publication status	Published - 1 Apr 2021

Bibliographical note

Acknowledgments
We would like to thank Dr. Kirsten van Lom, Dr. Eric Braakman, Lucia Duinhouwer, and Mariëtte ter Borg for providing CD34+ cells and help with human BM sampling; Natalie Papazian for helping to process fetal tissue; Dr. Elwin Rombouts, Peter van Geel, and Michael Vermeulen for operating the BD FACSARIA III; Maria Mylona, Maria Adisty, and Paulette van Strien for performing FACs and RNA-seq; Onno Roovers, Almira Henić, Eline Pronk, Gert-Jan Kremers, Bella Banjanin, Ursula Stalmann, Nils Bayer, and Madelon de Jong for providing technical advice and assistance; Esther Siteur-van Rijnstra and Cynthia van der Linden for providing technical assistance with fetal tissue; Mathias Francois and lab members for help with the lineage tracing experiments; Emma de Pater for advice concerning mouse breeding; members of the Erasmus MC Department of Hematology for scientific discussions; and Egied Simons for assisting with illustrations. This work was supported by an Erasmus MC fellowship award (to M.H.G.P.R.). M.-J.G. and G.S.-D. are supported by the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation , Dutch Federation of University Medical Centers , Netherlands Organization for Health Research and Development , and the Royal Netherlands Academy of Sciences (grant CVON 2014-11 RECONNECT). G.S.-D. is also sponsored by a trampoline grant (# 22379 ) from AFM-Telethon and FOP Italia (Grant Italia 2020 ). A.L. is supported by the European Union Horizon 2020 Research and Innovation Program under grant agreement 801159 .

Publisher Copyright: © 2021 Elsevier Inc.

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Kenswil, K. J. G., Pisterzi, P., Sánchez-Duffhues, G., van Dijk, C., Lolli, A., Knuth, C., Vanchin, B., Jaramillo, A. C., Hoogenboezem, R. M., Sanders, M. A., Feyen, J., Cupedo, T., Costa, I. G., Li, R., Bindels, E. M. J., Lodder, K., Blom, B., Bos, P. K., Goumans, M. J., ... Raaijmakers, M. H. G. P. (2021). Endothelium-derived stromal cells contribute to hematopoietic bone marrow niche formation. Cell Stem Cell, 28(4), 653-670.e11. https://doi.org/10.1016/j.stem.2021.01.006

@article{03e0163568464ac59f87b6a19659dbf5,

title = "Endothelium-derived stromal cells contribute to hematopoietic bone marrow niche formation",

abstract = "Bone marrow stromal cells (BMSCs) play pivotal roles in tissue maintenance and regeneration. Their origins, however, remain incompletely understood. Here we identify rare LNGFR+ cells in human fetal and regenerative bone marrow that co-express endothelial and stromal markers. This endothelial subpopulation displays transcriptional reprogramming consistent with endothelial-to-mesenchymal transition (EndoMT) and can generate multipotent stromal cells that reconstitute the bone marrow (BM) niche upon transplantation. Single-cell transcriptomics and lineage tracing in mice confirm robust and sustained contributions of EndoMT to bone precursor and hematopoietic niche pools. Interleukin-33 (IL-33) is overexpressed in subsets of EndoMT cells and drives this conversion process through ST2 receptor signaling. These data reveal generation of tissue-forming BMSCs from mouse and human endothelial cells and may be instructive for approaches to human tissue regeneration.",

author = "Kenswil, {Keane Jared Guillaume} and Paola Pisterzi and Gonzalo S{\'a}nchez-Duffhues and {van Dijk}, Claire and Andrea Lolli and Callie Knuth and Byambasuren Vanchin and Jaramillo, {Adrian Christopher} and Hoogenboezem, {Remco Michiel} and Sanders, {Mathijs Arnoud} and Jacqueline Feyen and Tom Cupedo and Costa, {Ivan G.} and Ronghui Li and Bindels, {Eric Moniqu{\'e} Johannes} and Kirsten Lodder and Bianca Blom and Bos, {Pieter Koen} and Goumans, {Marie Jos{\'e}} and {ten Dijke}, Peter and Eric Farrell and Guido Krenning and Raaijmakers, {Marc Hermanus Gerardus Petrus}",

note = "Acknowledgments We would like to thank Dr. Kirsten van Lom, Dr. Eric Braakman, Lucia Duinhouwer, and Mari{\"e}tte ter Borg for providing CD34+ cells and help with human BM sampling; Natalie Papazian for helping to process fetal tissue; Dr. Elwin Rombouts, Peter van Geel, and Michael Vermeulen for operating the BD FACSARIA III; Maria Mylona, Maria Adisty, and Paulette van Strien for performing FACs and RNA-seq; Onno Roovers, Almira Heni{\'c}, Eline Pronk, Gert-Jan Kremers, Bella Banjanin, Ursula Stalmann, Nils Bayer, and Madelon de Jong for providing technical advice and assistance; Esther Siteur-van Rijnstra and Cynthia van der Linden for providing technical assistance with fetal tissue; Mathias Francois and lab members for help with the lineage tracing experiments; Emma de Pater for advice concerning mouse breeding; members of the Erasmus MC Department of Hematology for scientific discussions; and Egied Simons for assisting with illustrations. This work was supported by an Erasmus MC fellowship award (to M.H.G.P.R.). M.-J.G. and G.S.-D. are supported by the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation , Dutch Federation of University Medical Centers , Netherlands Organization for Health Research and Development , and the Royal Netherlands Academy of Sciences (grant CVON 2014-11 RECONNECT). G.S.-D. is also sponsored by a trampoline grant (# 22379 ) from AFM-Telethon and FOP Italia (Grant Italia 2020 ). A.L. is supported by the European Union Horizon 2020 Research and Innovation Program under grant agreement 801159 . Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = apr,

day = "1",

doi = "10.1016/j.stem.2021.01.006",

language = "English",

volume = "28",

pages = "653--670.e11",

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Kenswil, KJG, Pisterzi, P, Sánchez-Duffhues, G, van Dijk, C , Lolli, A, Knuth, C, Vanchin, B, Jaramillo, AC, Hoogenboezem, RM , Sanders, MA , Feyen, J , Cupedo, T, Costa, IG, Li, R, Bindels, EMJ, Lodder, K, Blom, B, Bos, PK, Goumans, MJ, ten Dijke, P, Farrell, E, Krenning, G & Raaijmakers, MHGP 2021, 'Endothelium-derived stromal cells contribute to hematopoietic bone marrow niche formation', Cell Stem Cell, vol. 28, no. 4, pp. 653-670.e11. https://doi.org/10.1016/j.stem.2021.01.006

TY - JOUR

T1 - Endothelium-derived stromal cells contribute to hematopoietic bone marrow niche formation

AU - Kenswil, Keane Jared Guillaume

AU - Pisterzi, Paola

AU - Sánchez-Duffhues, Gonzalo

AU - van Dijk, Claire

AU - Lolli, Andrea

AU - Knuth, Callie

AU - Vanchin, Byambasuren

AU - Jaramillo, Adrian Christopher

AU - Hoogenboezem, Remco Michiel

AU - Sanders, Mathijs Arnoud

AU - Feyen, Jacqueline

AU - Cupedo, Tom

AU - Costa, Ivan G.

AU - Li, Ronghui

AU - Bindels, Eric Moniqué Johannes

AU - Lodder, Kirsten

AU - Blom, Bianca

AU - Bos, Pieter Koen

AU - Goumans, Marie José

AU - ten Dijke, Peter

AU - Farrell, Eric

AU - Krenning, Guido

AU - Raaijmakers, Marc Hermanus Gerardus Petrus

N1 - Acknowledgments We would like to thank Dr. Kirsten van Lom, Dr. Eric Braakman, Lucia Duinhouwer, and Mariëtte ter Borg for providing CD34+ cells and help with human BM sampling; Natalie Papazian for helping to process fetal tissue; Dr. Elwin Rombouts, Peter van Geel, and Michael Vermeulen for operating the BD FACSARIA III; Maria Mylona, Maria Adisty, and Paulette van Strien for performing FACs and RNA-seq; Onno Roovers, Almira Henić, Eline Pronk, Gert-Jan Kremers, Bella Banjanin, Ursula Stalmann, Nils Bayer, and Madelon de Jong for providing technical advice and assistance; Esther Siteur-van Rijnstra and Cynthia van der Linden for providing technical assistance with fetal tissue; Mathias Francois and lab members for help with the lineage tracing experiments; Emma de Pater for advice concerning mouse breeding; members of the Erasmus MC Department of Hematology for scientific discussions; and Egied Simons for assisting with illustrations. This work was supported by an Erasmus MC fellowship award (to M.H.G.P.R.). M.-J.G. and G.S.-D. are supported by the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation , Dutch Federation of University Medical Centers , Netherlands Organization for Health Research and Development , and the Royal Netherlands Academy of Sciences (grant CVON 2014-11 RECONNECT). G.S.-D. is also sponsored by a trampoline grant (# 22379 ) from AFM-Telethon and FOP Italia (Grant Italia 2020 ). A.L. is supported by the European Union Horizon 2020 Research and Innovation Program under grant agreement 801159 . Publisher Copyright: © 2021 Elsevier Inc.

PY - 2021/4/1

Y1 - 2021/4/1

N2 - Bone marrow stromal cells (BMSCs) play pivotal roles in tissue maintenance and regeneration. Their origins, however, remain incompletely understood. Here we identify rare LNGFR+ cells in human fetal and regenerative bone marrow that co-express endothelial and stromal markers. This endothelial subpopulation displays transcriptional reprogramming consistent with endothelial-to-mesenchymal transition (EndoMT) and can generate multipotent stromal cells that reconstitute the bone marrow (BM) niche upon transplantation. Single-cell transcriptomics and lineage tracing in mice confirm robust and sustained contributions of EndoMT to bone precursor and hematopoietic niche pools. Interleukin-33 (IL-33) is overexpressed in subsets of EndoMT cells and drives this conversion process through ST2 receptor signaling. These data reveal generation of tissue-forming BMSCs from mouse and human endothelial cells and may be instructive for approaches to human tissue regeneration.

AB - Bone marrow stromal cells (BMSCs) play pivotal roles in tissue maintenance and regeneration. Their origins, however, remain incompletely understood. Here we identify rare LNGFR+ cells in human fetal and regenerative bone marrow that co-express endothelial and stromal markers. This endothelial subpopulation displays transcriptional reprogramming consistent with endothelial-to-mesenchymal transition (EndoMT) and can generate multipotent stromal cells that reconstitute the bone marrow (BM) niche upon transplantation. Single-cell transcriptomics and lineage tracing in mice confirm robust and sustained contributions of EndoMT to bone precursor and hematopoietic niche pools. Interleukin-33 (IL-33) is overexpressed in subsets of EndoMT cells and drives this conversion process through ST2 receptor signaling. These data reveal generation of tissue-forming BMSCs from mouse and human endothelial cells and may be instructive for approaches to human tissue regeneration.

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U2 - 10.1016/j.stem.2021.01.006

DO - 10.1016/j.stem.2021.01.006

M3 - Article

C2 - 33561425

AN - SCOPUS:85101671588

SN - 1934-5909

VL - 28

SP - 653-670.e11

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 4

ER -

Endothelium-derived stromal cells contribute to hematopoietic bone marrow niche formation

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