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Functional and molecular profiling of hematopoietic stem cells during regeneration

Rydström, Anna LU ; Grahn, Tan H.M. LU orcid ; Niroula, Abhishek LU ; Mansell, Els LU ; van der Garde, Mark LU ; Pertesi, Maroulio LU ; Subramaniam, Agatheeswaran LU ; Soneji, Shamit LU ; Zubarev, Roman and Enver, Tariq LU , et al. (2023) In Experimental Hematology 127. p.40-51
Abstract

Hematopoietic stem cells (HSCs) enable hematopoietic stem cell transplantation (HCT) through their ability to replenish the entire blood system. Proliferation of HSCs is linked to decreased reconstitution potential, and a precise regulation of actively dividing HSCs is thus essential to ensure long-term functionality. This regulation becomes important in the transplantation setting where HSCs undergo proliferation followed by a gradual transition to quiescence and homeostasis. Although mouse HSCs have been well studied under homeostatic conditions, the mechanisms regulating HSC activation under stress remain unclear. Here, we analyzed the different phases of regeneration after transplantation. We isolated bone marrow from mice at 8 time... (More)

Hematopoietic stem cells (HSCs) enable hematopoietic stem cell transplantation (HCT) through their ability to replenish the entire blood system. Proliferation of HSCs is linked to decreased reconstitution potential, and a precise regulation of actively dividing HSCs is thus essential to ensure long-term functionality. This regulation becomes important in the transplantation setting where HSCs undergo proliferation followed by a gradual transition to quiescence and homeostasis. Although mouse HSCs have been well studied under homeostatic conditions, the mechanisms regulating HSC activation under stress remain unclear. Here, we analyzed the different phases of regeneration after transplantation. We isolated bone marrow from mice at 8 time points after transplantation and examined the reconstitution dynamics and transcriptional profiles of stem and progenitor populations. We found that regenerating HSCs initially produced rapidly expanding progenitors and displayed distinct changes in fatty acid metabolism and glycolysis. Moreover, we observed molecular changes in cell cycle, MYC and mTOR signaling in both HSCs, and progenitor subsets. We used a decay rate model to fit the temporal transcription profiles of regenerating HSCs and identified genes with progressively decreased or increased expression after transplantation. These genes overlapped to a large extent with published gene sets associated with key aspects of HSC function, demonstrating the potential of this data set as a resource for identification of novel HSC regulators. Taken together, our study provides a detailed functional and molecular characterization of HSCs at different phases of regeneration and identifies a gene set associated with the transition from proliferation to quiescence.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Experimental Hematology
volume
127
pages
40 - 51
publisher
Elsevier
external identifiers
  • scopus:85172069729
  • pmid:37666355
ISSN
0301-472X
DOI
10.1016/j.exphem.2023.08.010
language
English
LU publication?
yes
additional info
Funding Information: This work was funded by Knut och Alice Wallenbergs Stiftelse . Additionally, the Swedish Research Council, Cancerfonden , and the Swedish Pediatric Cancer Society funded the study with grants to Dr. SK. This work was supported by Core-to-Core Program Advanced Research Networks “Integrative approach for normal and leukemic stem cells” from the Japan Society for the Promotion of Science of Japan. We thank Alexandra Rundberg-Nilsson for valuable input on the manuscript. Publisher Copyright: © 2023 ISEH -- Society for Hematology and Stem Cells
id
2247a811-37cb-409c-a3f1-ad04f3662c5a
date added to LUP
2023-12-12 13:38:27
date last changed
2024-12-06 07:18:25
@article{2247a811-37cb-409c-a3f1-ad04f3662c5a,
  abstract     = {{<p>Hematopoietic stem cells (HSCs) enable hematopoietic stem cell transplantation (HCT) through their ability to replenish the entire blood system. Proliferation of HSCs is linked to decreased reconstitution potential, and a precise regulation of actively dividing HSCs is thus essential to ensure long-term functionality. This regulation becomes important in the transplantation setting where HSCs undergo proliferation followed by a gradual transition to quiescence and homeostasis. Although mouse HSCs have been well studied under homeostatic conditions, the mechanisms regulating HSC activation under stress remain unclear. Here, we analyzed the different phases of regeneration after transplantation. We isolated bone marrow from mice at 8 time points after transplantation and examined the reconstitution dynamics and transcriptional profiles of stem and progenitor populations. We found that regenerating HSCs initially produced rapidly expanding progenitors and displayed distinct changes in fatty acid metabolism and glycolysis. Moreover, we observed molecular changes in cell cycle, MYC and mTOR signaling in both HSCs, and progenitor subsets. We used a decay rate model to fit the temporal transcription profiles of regenerating HSCs and identified genes with progressively decreased or increased expression after transplantation. These genes overlapped to a large extent with published gene sets associated with key aspects of HSC function, demonstrating the potential of this data set as a resource for identification of novel HSC regulators. Taken together, our study provides a detailed functional and molecular characterization of HSCs at different phases of regeneration and identifies a gene set associated with the transition from proliferation to quiescence.</p>}},
  author       = {{Rydström, Anna and Grahn, Tan H.M. and Niroula, Abhishek and Mansell, Els and van der Garde, Mark and Pertesi, Maroulio and Subramaniam, Agatheeswaran and Soneji, Shamit and Zubarev, Roman and Enver, Tariq and Nilsson, Björn and Miharada, Kenichi and Larsson, Jonas and Karlsson, Stefan}},
  issn         = {{0301-472X}},
  language     = {{eng}},
  pages        = {{40--51}},
  publisher    = {{Elsevier}},
  series       = {{Experimental Hematology}},
  title        = {{Functional and molecular profiling of hematopoietic stem cells during regeneration}},
  url          = {{http://dx.doi.org/10.1016/j.exphem.2023.08.010}},
  doi          = {{10.1016/j.exphem.2023.08.010}},
  volume       = {{127}},
  year         = {{2023}},
}