Schlafen2 is a regulator of quiescence in adult murine hematopoietic stem cells
(2022) In Haematologica 107(12). p.2884-2896- Abstract
Even though hematopoietic stem cells (HSC) are characterized by their ability to self-renew and differentiate, they primarily reside in quiescence. Despite the immense importance of this quiescent state, its maintenance and regulation is still incompletely understood. Schlafen2 (Slfn2) is a cytoplasmic protein known to be involved in cell proliferation, differentiation, quiescence, interferon response, and regulation of the immune system. Interestingly, Slfn2 is highly expressed in primitive hematopoietic cells. In order to investigate the role of Slfn2 in the regulation of HSC we have studied HSC function in the elektra mouse model, where the elektra allele of the Slfn2 gene contains a point mutation causing loss of function of the... (More)
Even though hematopoietic stem cells (HSC) are characterized by their ability to self-renew and differentiate, they primarily reside in quiescence. Despite the immense importance of this quiescent state, its maintenance and regulation is still incompletely understood. Schlafen2 (Slfn2) is a cytoplasmic protein known to be involved in cell proliferation, differentiation, quiescence, interferon response, and regulation of the immune system. Interestingly, Slfn2 is highly expressed in primitive hematopoietic cells. In order to investigate the role of Slfn2 in the regulation of HSC we have studied HSC function in the elektra mouse model, where the elektra allele of the Slfn2 gene contains a point mutation causing loss of function of the Slfn2 protein. We found that homozygosity for the elektra allele caused a decrease of primitive hematopoietic compartments in murine bone marrow. We further found that transplantation of elektra bone marrow and purified HSC resulted in a significantly reduced regenerative capacity of HSC in competitive transplantation settings. Importantly, we found that a significantly higher fraction of elektra HSC (as compared to wild-type HSC) were actively cycling, suggesting that the mutation in Slfn2 increases HSC proliferation. This additionally caused an increased amount of apoptotic stem and progenitor cells. Taken together, our findings demonstrate that dysregulation of Slfn2 results in a functional deficiency of primitive hematopoietic cells, which is particularly reflected by a drastically impaired ability to reconstitute the hematopoietic system following transplantation and an increase in HSC proliferation. This study thus identifies Slfn2 as a novel and critical regulator of adult HSC and HSC quiescence.
(Less)
- author
- Warsi, Sarah
LU
; Dahl, Maria
LU
; Smith, Emma M.K.
LU
; Rydström, Anna
LU
; Mansell, Els
LU
; Sigurdsson, Valgardur
LU
; Sjöberg, Julia
LU
; Soneji, Shamit
LU
; Rörby, Emma
LU
; Siva, Kavitha
LU
; Grahn, Tan H.M.
LU
; Liu, Yang
LU
; Blank, Ulrika
; Karlsson, Göran
LU
and Karlsson, Stefan
LU
(Less) - organization
- publishing date
- 2022
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Haematologica
- volume
- 107
- issue
- 12
- pages
- 13 pages
- publisher
- Ferrata Storti Foundation
- external identifiers
-
- scopus:85143181058
- pmid:35615926
- ISSN
- 0390-6078
- DOI
- 10.3324/haematol.2021.279799
- language
- English
- LU publication?
- yes
- id
- f9f8e913-04d5-46d4-ae76-1cf153a6f9ad
- date added to LUP
- 2022-12-23 10:19:44
- date last changed
- 2024-04-16 18:36:22
@article{f9f8e913-04d5-46d4-ae76-1cf153a6f9ad,
abstract = {{<p>Even though hematopoietic stem cells (HSC) are characterized by their ability to self-renew and differentiate, they primarily reside in quiescence. Despite the immense importance of this quiescent state, its maintenance and regulation is still incompletely understood. Schlafen2 (Slfn2) is a cytoplasmic protein known to be involved in cell proliferation, differentiation, quiescence, interferon response, and regulation of the immune system. Interestingly, Slfn2 is highly expressed in primitive hematopoietic cells. In order to investigate the role of Slfn2 in the regulation of HSC we have studied HSC function in the elektra mouse model, where the elektra allele of the Slfn2 gene contains a point mutation causing loss of function of the Slfn2 protein. We found that homozygosity for the elektra allele caused a decrease of primitive hematopoietic compartments in murine bone marrow. We further found that transplantation of elektra bone marrow and purified HSC resulted in a significantly reduced regenerative capacity of HSC in competitive transplantation settings. Importantly, we found that a significantly higher fraction of elektra HSC (as compared to wild-type HSC) were actively cycling, suggesting that the mutation in Slfn2 increases HSC proliferation. This additionally caused an increased amount of apoptotic stem and progenitor cells. Taken together, our findings demonstrate that dysregulation of Slfn2 results in a functional deficiency of primitive hematopoietic cells, which is particularly reflected by a drastically impaired ability to reconstitute the hematopoietic system following transplantation and an increase in HSC proliferation. This study thus identifies Slfn2 as a novel and critical regulator of adult HSC and HSC quiescence.</p>}},
author = {{Warsi, Sarah and Dahl, Maria and Smith, Emma M.K. and Rydström, Anna and Mansell, Els and Sigurdsson, Valgardur and Sjöberg, Julia and Soneji, Shamit and Rörby, Emma and Siva, Kavitha and Grahn, Tan H.M. and Liu, Yang and Blank, Ulrika and Karlsson, Göran and Karlsson, Stefan}},
issn = {{0390-6078}},
language = {{eng}},
number = {{12}},
pages = {{2884--2896}},
publisher = {{Ferrata Storti Foundation}},
series = {{Haematologica}},
title = {{Schlafen2 is a regulator of quiescence in adult murine hematopoietic stem cells}},
url = {{http://dx.doi.org/10.3324/haematol.2021.279799}},
doi = {{10.3324/haematol.2021.279799}},
volume = {{107}},
year = {{2022}},
}