Prospective isolation of radiation induced erythroid stress progenitors reveals unique transcriptomic and epigenetic signatures enabling increased erythroid output
(2020) In Haematologica 105(11). p.2561-2571- Abstract
Massive expansion of erythroid progenitor cells is essential for surviving anemic stress. Research towards understanding this critical process, referred to as stress-erythropoiesis, has been hampered due to the lack of specific marker-combinations enabling analysis of the distinct stress-progenitor cells capable of providing radioprotection and enhanced red blood cell production. Here we present a method for the precise identification and in vivo validation of progenitor cells contributing to both steady-state and stress-erythropoiesis, enabling for the first time in-depth molecular characterization of these cells. Differential expression of surface markers CD150, CD9 and Sca1 defines a hierarchy of splenic stress-progenitors during... (More)
Massive expansion of erythroid progenitor cells is essential for surviving anemic stress. Research towards understanding this critical process, referred to as stress-erythropoiesis, has been hampered due to the lack of specific marker-combinations enabling analysis of the distinct stress-progenitor cells capable of providing radioprotection and enhanced red blood cell production. Here we present a method for the precise identification and in vivo validation of progenitor cells contributing to both steady-state and stress-erythropoiesis, enabling for the first time in-depth molecular characterization of these cells. Differential expression of surface markers CD150, CD9 and Sca1 defines a hierarchy of splenic stress-progenitors during irradiation-induced stress recovery in mice, and provides high-purity isolation of the functional stress erythroid burst-forming-units (stress-BFU-E) with a 100-fold improved enrichment compared to the state-of-the-art. By transplanting purified stress-progenitors expressing the fluorescent protein Kusabira Orange, we determined their kinetics in vivo and demonstrated that CD150+CD9+Sca1 -stress-BFU-E provide a massive but transient radioprotective erythroid wave, followed by multi-lineage reconstitution from CD150+CD9+Sca1+ multi-potent stem/progenitor cells. Whole genome transcriptional analysis revealed that stress-BFU-E express gene signatures more associated with erythropoiesis and proliferation compared to steady-state BFU-E, and are bone morphogenetic protein 4-responsive. Evaluation of chromatin accessibility through ATAC sequencing reveals enhanced and differential accessibility to binding sites of the chromatin-looping transcription factor CTCF in stress-BFU-E compared to steady-state BFU-E. Our findings offer a molecular insight into the unique capacity of stress-BFU-E to rapidly form erythroid cells in response to anemia and constitute an important step towards identifying novel erythropoiesis stimulating agents.
(Less)
- author
- Singbrant, Sofie LU ; Mattebo, Alexander LU ; Sigvardsson, Mikael LU ; Strid, Tobias LU and Flygare, Johan LU
- organization
- publishing date
- 2020
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Haematologica
- volume
- 105
- issue
- 11
- pages
- 11 pages
- publisher
- Ferrata Storti Foundation
- external identifiers
-
- pmid:31919074
- scopus:85088967800
- ISSN
- 0390-6078
- DOI
- 10.3324/haematol.2019.234542
- language
- English
- LU publication?
- yes
- id
- 6cb0cd3a-f617-40bc-ae0b-a352631c9f23
- date added to LUP
- 2021-01-04 11:55:51
- date last changed
- 2024-03-05 16:47:06
@article{6cb0cd3a-f617-40bc-ae0b-a352631c9f23,
abstract = {{<p>Massive expansion of erythroid progenitor cells is essential for surviving anemic stress. Research towards understanding this critical process, referred to as stress-erythropoiesis, has been hampered due to the lack of specific marker-combinations enabling analysis of the distinct stress-progenitor cells capable of providing radioprotection and enhanced red blood cell production. Here we present a method for the precise identification and in vivo validation of progenitor cells contributing to both steady-state and stress-erythropoiesis, enabling for the first time in-depth molecular characterization of these cells. Differential expression of surface markers CD150, CD9 and Sca1 defines a hierarchy of splenic stress-progenitors during irradiation-induced stress recovery in mice, and provides high-purity isolation of the functional stress erythroid burst-forming-units (stress-BFU-E) with a 100-fold improved enrichment compared to the state-of-the-art. By transplanting purified stress-progenitors expressing the fluorescent protein Kusabira Orange, we determined their kinetics in vivo and demonstrated that CD150<sup>+</sup>CD9<sup>+</sup>Sca1 -stress-BFU-E provide a massive but transient radioprotective erythroid wave, followed by multi-lineage reconstitution from CD150<sup>+</sup>CD9<sup>+</sup>Sca1<sup>+</sup> multi-potent stem/progenitor cells. Whole genome transcriptional analysis revealed that stress-BFU-E express gene signatures more associated with erythropoiesis and proliferation compared to steady-state BFU-E, and are bone morphogenetic protein 4-responsive. Evaluation of chromatin accessibility through ATAC sequencing reveals enhanced and differential accessibility to binding sites of the chromatin-looping transcription factor CTCF in stress-BFU-E compared to steady-state BFU-E. Our findings offer a molecular insight into the unique capacity of stress-BFU-E to rapidly form erythroid cells in response to anemia and constitute an important step towards identifying novel erythropoiesis stimulating agents.</p>}},
author = {{Singbrant, Sofie and Mattebo, Alexander and Sigvardsson, Mikael and Strid, Tobias and Flygare, Johan}},
issn = {{0390-6078}},
language = {{eng}},
number = {{11}},
pages = {{2561--2571}},
publisher = {{Ferrata Storti Foundation}},
series = {{Haematologica}},
title = {{Prospective isolation of radiation induced erythroid stress progenitors reveals unique transcriptomic and epigenetic signatures enabling increased erythroid output}},
url = {{http://dx.doi.org/10.3324/haematol.2019.234542}},
doi = {{10.3324/haematol.2019.234542}},
volume = {{105}},
year = {{2020}},
}