TY - JOUR
T1 - Deconvolution of the hematopoietic stem cell microenvironment reveals a high degree of specialization and conservation
AU - Ye, Jin
AU - Calvo, Isabel A.
AU - Cenzano, Itziar
AU - Vilas, Amaia
AU - Martinez-de-Morentin, Xabier
AU - Lasaga, Miren
AU - Alignani, Diego
AU - Paiva, Bruno
AU - Viñado, Ana C.
AU - San Martin-Uriz, Patxi
AU - Romero, Juan P.
AU - Quilez Agreda, Delia
AU - Miñana Barrios, Marta
AU - Sancho-González, Ignacio
AU - Todisco, Gabriele
AU - Malcovati, Luca
AU - Planell, Nuria
AU - Saez, Borja
AU - Tegner, Jesper N.
AU - Prosper, Felipe
AU - Gomez-Cabrero, David
N1 - Funding Information:
This research was funded by grants from The Spanish Government , through project PID2019-111192GA-I00 ( MICINN ) to DGC. Instituto de Salud Carlos III ( ISCIII ) and co-financed by FEDER : PI16/02024 , PI17/00701 and PI19/01352 , TRANSCAN EPICA AC16/00041 , CIBERONC CB16/12/00489 ; Redes de Investigación Cooperativa (TERCEL RD16/0011/0005 ); Spanish Ministry of Economy, Industry and Competitivity ( RTHALMY SAF2017-92632-EXP ); Departamento de Salud, Gobierno de Navarra 40/2016 and Departamento de Desarrollo Económico y Empresarial ( AGATA 0011-1411-2020-000010 and 0011-1411-2020-000013 ). The study was also supported by Cancer Research UK [ C355/A26819 ] and Cancer Research UK , FCAECC and AIRC under the Accelerator Award Program (EDITOR), the Multiple Myeloma Research Foundation Networks of excellence 2017 Immunotherapy Program Grant Award, the International Myeloma Foundation ( Brian van Novis ), and Paula and Rodger Riney Foundation to FP. Instituto de Salud Carlos III ( ISCIII ) ( PI17/01346 and PI20/00152 ), co-funded by the ERDF (A way to make Europe); FC-AECC ( AIO16163636SAEZ ); Gobierno de Navarra ( 0011-3638-2020-000011 ) co-funded by the ERDF through the Operative Program 2014–2020 of Navarra and Gobierno de Navarra ( 0011-3597-2020-000005 ) to BS. G.T. was supported by the Associazione Italiana per la Ricerca sul Cancro ( AIRC ), 5x1000 Program (Project #21267). IC was supported by Juan de la Cierva grant from Ministerio de Ciencia , Innovación y Universidades , Gobierno de España , Sara Borrell award from Instituto de Salud Carlos III ( ISCIII ) and Marie Curie grant ( H2020-MSCA-IF-837491 ) from European Commission . ICA was supported by AECC predoctoral fellowship . NP was supported by Juan de la Cierva grant from Ministerio de Ciencia , Innovación y Universidades , Gobierno de España ( FJC2019-042304-I ). L.M. was supported by the Associazione Italiana per la Ricerca sul Cancro ( AIRC ) 5x1000 Program (Project #21267) and Investigator Grant 2017 (Project #20125), and by Cancer Research UK , FCAECC and AIRC Accelerator Award Program (Project # C355/A26819 and # 22796 ).
Funding Information:
We would like to thank the staff of the flow cytometry core, the advances genomic lab, and the animal facility at CIMA Universidad de Navarra for their invaluable technical and intellectual assistance. We are particularly grateful to the healthy volunteers who donated bone marrow tissue for this study. We also acknowledge Ali O. Balubaid's help in writing. We would like to acknowledge Miguel Cocera-Fernandez's contribution to the Graphical Abstract. This research was funded by grants from The Spanish Government, through project PID2019-111192GA-I00 (MICINN) to DGC. Instituto de Salud Carlos III (ISCIII) and co-financed by FEDER: PI16/02024, PI17/00701 and PI19/01352, TRANSCAN EPICA AC16/00041, CIBERONC CB16/12/00489; Redes de Investigaci?n Cooperativa (TERCEL RD16/0011/0005); Spanish Ministry of Economy, Industry and Competitivity (RTHALMY SAF2017-92632-EXP); Departamento de Salud, Gobierno de Navarra 40/2016 and Departamento de Desarrollo Econ?mico y Empresarial (AGATA 0011-1411-2020-000010 and 0011-1411-2020-000013). The study was also supported by Cancer Research UK [C355/A26819] and Cancer Research UK, FCAECC and AIRC under the Accelerator Award Program (EDITOR), the Multiple Myeloma Research Foundation Networks of excellence 2017 Immunotherapy Program Grant Award, the International Myeloma Foundation (Brian van Novis), and Paula and Rodger Riney Foundation to FP. Instituto de Salud Carlos III (ISCIII) (PI17/01346 and PI20/00152), co-funded by the ERDF (A way to make Europe); FC-AECC (AIO16163636SAEZ); Gobierno de Navarra (0011-3638-2020-000011) co-funded by the ERDF through the Operative Program 2014?2020 of Navarra and Gobierno de Navarra (0011-3597-2020-000005) to BS. G.T. was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC), 5x1000 Program (Project #21267). IC was supported by Juan de la Cierva grant from Ministerio de Ciencia, Innovaci?n y Universidades, Gobierno de Espa?a, Sara Borrell award from Instituto de Salud Carlos III (ISCIII) and Marie Curie grant (H2020-MSCA-IF-837491) from European Commission. ICA was supported by AECC predoctoral fellowship. NP was supported by Juan de la Cierva grant from Ministerio de Ciencia, Innovaci?n y Universidades, Gobierno de Espa?a (FJC2019-042304-I). L.M. was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) 5x1000 Program (Project #21267) and Investigator Grant 2017 (Project #20125), and by Cancer Research UK, FCAECC and AIRC Accelerator Award Program (Project #C355/A26819 and #22796). B.S. J.T. F.P. and D.G.C. conceived and directed the research project. I.A.C. and B.S. designed the research experiments. I.A.C. with help from I.C. performed the isolation and FACS sorting of BM cells. J.Y. performed all the computational experiments, and analyzed the data with help from X.M.M. M.L. and N.P. A.V. performed the scRNA-Seq experiments. B.S. and D.G.C. supervised the work. All authors actively participated in the discussions underlying this manuscript. I.A.C. I.C. J.Y. B.S. and D.G.C. discussed the results and wrote the final manuscript with input from J.T. and F.P. All authors contributed to, read and approved the final manuscript. The authors declare no competing interests.
Publisher Copyright:
© 2022 The Authors
PY - 2022/5/20
Y1 - 2022/5/20
N2 - Understanding the regulation of normal and malignant human hematopoiesis requires comprehensive cell atlas of the hematopoietic stem cell (HSC) regulatory microenvironment. Here, we develop a tailored bioinformatic pipeline to integrate public and proprietary single-cell RNA sequencing (scRNA-seq) datasets. As a result, we robustly identify for the first time 14 intermediate cell states and 11 stages of differentiation in the endothelial and mesenchymal BM compartments, respectively. Our data provide the most comprehensive description to date of the murine HSC-regulatory microenvironment and suggest a higher level of specialization of the cellular circuits than previously anticipated. Furthermore, this deep characterization allows inferring conserved features in human, suggesting that the layers of microenvironmental regulation of hematopoiesis may also be shared between species. Our resource and methodology is a stepping-stone toward a comprehensive cell atlas of the BM microenvironment.
AB - Understanding the regulation of normal and malignant human hematopoiesis requires comprehensive cell atlas of the hematopoietic stem cell (HSC) regulatory microenvironment. Here, we develop a tailored bioinformatic pipeline to integrate public and proprietary single-cell RNA sequencing (scRNA-seq) datasets. As a result, we robustly identify for the first time 14 intermediate cell states and 11 stages of differentiation in the endothelial and mesenchymal BM compartments, respectively. Our data provide the most comprehensive description to date of the murine HSC-regulatory microenvironment and suggest a higher level of specialization of the cellular circuits than previously anticipated. Furthermore, this deep characterization allows inferring conserved features in human, suggesting that the layers of microenvironmental regulation of hematopoiesis may also be shared between species. Our resource and methodology is a stepping-stone toward a comprehensive cell atlas of the BM microenvironment.
KW - Biological sciences
KW - Omics
KW - Stem cells research
KW - Transcriptomics
UR - http://www.scopus.com/inward/record.url?scp=85129539814&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2022.104225
DO - 10.1016/j.isci.2022.104225
M3 - Article
C2 - 35494238
AN - SCOPUS:85129539814
SN - 2589-0042
VL - 25
JO - iScience
JF - iScience
IS - 5
M1 - 104225
ER -