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S100A6 is a critical regulator of hematopoietic stem cells.

Tan Grahn, Hooi Min LU orcid ; Niroula, Abhishek LU ; Vegvari, Akos ; Oburoglu, Leal LU orcid ; Pertesi, Maroulio LU ; Warsi, Sarah LU ; Safi, Fatemeh LU ; Miharada, Natsumi LU ; C. Garcia, Sandra LU and Siva, Kavitha LU , et al. (2020) In Leukemia
Abstract
The fate options of hematopoietic stem cells (HSCs) include self-renewal, differentiation, migration, and apoptosis. HSCs self-renewal divisions in stem cells are required for rapid regeneration during tissue damage and stress, but how precisely intracellular calcium signals are regulated to maintain fate options in normal hematopoiesis is unclear. S100A6 knockout (KO) HSCs have reduced total cell numbers in the HSC compartment, decreased myeloid output, and increased apoptotic HSC numbers in steady state. S100A6KO HSCs had impaired self-renewal and regenerative capacity, not responding to 5-Fluorouracil. Our transcriptomic and proteomic profiling suggested that S100A6 is a critical HSC regulator. Intriguingly, S100A6KO HSCs showed... (More)
The fate options of hematopoietic stem cells (HSCs) include self-renewal, differentiation, migration, and apoptosis. HSCs self-renewal divisions in stem cells are required for rapid regeneration during tissue damage and stress, but how precisely intracellular calcium signals are regulated to maintain fate options in normal hematopoiesis is unclear. S100A6 knockout (KO) HSCs have reduced total cell numbers in the HSC compartment, decreased myeloid output, and increased apoptotic HSC numbers in steady state. S100A6KO HSCs had impaired self-renewal and regenerative capacity, not responding to 5-Fluorouracil. Our transcriptomic and proteomic profiling suggested that S100A6 is a critical HSC regulator. Intriguingly, S100A6KO HSCs showed decreased levels of phosphorylated Akt (p-Akt) and Hsp90, with an impairment of mitochondrial respiratory capacity and a reduction of mitochondrial calcium levels. We showed that S100A6 regulates intracellular and mitochondria calcium buffering of HSC upon cytokine stimulation and have demonstrated that Akt activator SC79 reverts the levels of intracellular and mitochondrial calcium in HSC. Hematopoietic colony-forming activity and the Hsp90 activity of S100A6KO are restored through activation of the Akt pathway. We show that p-Akt is the prime downstream mechanism of S100A6 in the regulation of HSC self-renewal by specifically governing mitochondrial metabolic function and Hsp90 protein quality. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Leukemia
publisher
Nature Publishing Group
external identifiers
  • scopus:85086586391
  • pmid:32555370
ISSN
0887-6924
DOI
10.1038/s41375-020-0901-2
language
English
LU publication?
yes
id
08cecfe7-031d-4900-b4c0-7b9280d27f53
date added to LUP
2020-06-20 13:40:18
date last changed
2024-01-17 04:06:46
@article{08cecfe7-031d-4900-b4c0-7b9280d27f53,
  abstract     = {{The fate options of hematopoietic stem cells (HSCs) include self-renewal, differentiation, migration, and apoptosis. HSCs self-renewal divisions in stem cells are required for rapid regeneration during tissue damage and stress, but how precisely intracellular calcium signals are regulated to maintain fate options in normal hematopoiesis is unclear. S100A6 knockout (KO) HSCs have reduced total cell numbers in the HSC compartment, decreased myeloid output, and increased apoptotic HSC numbers in steady state. S100A6KO HSCs had impaired self-renewal and regenerative capacity, not responding to 5-Fluorouracil. Our transcriptomic and proteomic profiling suggested that S100A6 is a critical HSC regulator. Intriguingly, S100A6KO HSCs showed decreased levels of phosphorylated Akt (p-Akt) and Hsp90, with an impairment of mitochondrial respiratory capacity and a reduction of mitochondrial calcium levels. We showed that S100A6 regulates intracellular and mitochondria calcium buffering of HSC upon cytokine stimulation and have demonstrated that Akt activator SC79 reverts the levels of intracellular and mitochondrial calcium in HSC. Hematopoietic colony-forming activity and the Hsp90 activity of S100A6KO are restored through activation of the Akt pathway. We show that p-Akt is the prime downstream mechanism of S100A6 in the regulation of HSC self-renewal by specifically governing mitochondrial metabolic function and Hsp90 protein quality.}},
  author       = {{Tan Grahn, Hooi Min and Niroula, Abhishek and Vegvari, Akos and Oburoglu, Leal and Pertesi, Maroulio and Warsi, Sarah and Safi, Fatemeh and Miharada, Natsumi and C. Garcia, Sandra and Siva, Kavitha and Liu, Yang and Rörby, Emma and Nilsson, Björn and Zubarev, Roman A. and Karlsson, Stefan}},
  issn         = {{0887-6924}},
  language     = {{eng}},
  month        = {{06}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Leukemia}},
  title        = {{S100A6 is a critical regulator of hematopoietic stem cells.}},
  url          = {{http://dx.doi.org/10.1038/s41375-020-0901-2}},
  doi          = {{10.1038/s41375-020-0901-2}},
  year         = {{2020}},
}