Proteomic cornerstones of hematopoietic stem cell differentiation : distinct signatures of multipotent progenitors and myeloid committed cells
Klimmeck, Daniel ; Hansson, Jenny LU
; Raffel, Simon
; Vakhrushev, Sergey Y
; Trumpp, Andreas
and Krijgsveld, Jeroen
(2012)
In Molecular & Cellular Proteomics
11(8).
p.286-302
- Abstract
Regenerative tissues such as the skin epidermis, the intestinal mucosa or the hematopoietic system are organized in a hierarchical manner with stem cells building the top of this hierarchy. Somatic stem cells harbor the highest self-renewal activity and generate a series of multipotent progenitors which differentiate into lineage committed progenitors and subsequently mature cells. In this report, we applied an in-depth quantitative proteomic approach to analyze and compare the full proteomes of ex vivo isolated and FACS-sorted populations highly enriched for either multipotent hematopoietic stem/progenitor cells (HSPCs, Lin(neg)Sca-1(+)c-Kit(+)) or myeloid committed precursors (Lin(neg)Sca-1(-)c-Kit(+)). By employing stable isotope... (More)
Regenerative tissues such as the skin epidermis, the intestinal mucosa or the hematopoietic system are organized in a hierarchical manner with stem cells building the top of this hierarchy. Somatic stem cells harbor the highest self-renewal activity and generate a series of multipotent progenitors which differentiate into lineage committed progenitors and subsequently mature cells. In this report, we applied an in-depth quantitative proteomic approach to analyze and compare the full proteomes of ex vivo isolated and FACS-sorted populations highly enriched for either multipotent hematopoietic stem/progenitor cells (HSPCs, Lin(neg)Sca-1(+)c-Kit(+)) or myeloid committed precursors (Lin(neg)Sca-1(-)c-Kit(+)). By employing stable isotope dimethyl labeling and high-resolution mass spectrometry, more than 5000 proteins were quantified. From biological triplicate experiments subjected to rigorous statistical evaluation, 893 proteins were found differentially expressed between multipotent and myeloid committed cells. The differential protein content in these cell populations points to a distinct structural organization of the cytoskeleton including remodeling activity. In addition, we found a marked difference in the expression of metabolic enzymes, including a clear shift of specific protein isoforms of the glycolytic pathway. Proteins involved in translation showed a collective higher expression in myeloid progenitors, indicating an increased translational activity. Strikingly, the data uncover a unique signature related to immune defense mechanisms, centering on the RIG-I and type-1 interferon response systems, which are installed in multipotent progenitors but not evident in myeloid committed cells. This suggests that specific, and so far unrecognized, mechanisms protect these immature cells before they mature. In conclusion, this study indicates that the transition of hematopoietic stem/progenitors toward myeloid commitment is accompanied by a profound change in processing of cellular resources, adding novel insights into the molecular mechanisms at the interface between multipotency and lineage commitment.
(Less)
- author
- Klimmeck, Daniel
; Hansson, Jenny
LU
; Raffel, Simon
; Vakhrushev, Sergey Y
; Trumpp, Andreas
and Krijgsveld, Jeroen
- organization
- publishing date
- 2012-08
- type
- Contribution to journal
- publication status
- published
- keywords
- Animals, Cell Differentiation, Female, Flow Cytometry, Glycolysis, Hematopoiesis, Hematopoietic Stem Cells, Immunohistochemistry, Mice, Mice, Inbred C57BL, Multipotent Stem Cells, Myeloid Cells, Proteome, Proteomics, Spectrometry, Mass, Electrospray Ionization, Tandem Mass Spectrometry
- in
- Molecular & Cellular Proteomics
- volume
- 11
- issue
- 8
- pages
- 17 pages
- publisher
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- pmid:22454540
- scopus:84864805939
- ISSN
- 1535-9484
- DOI
- 10.1074/mcp.M111.016790
- language
- English
- LU publication?
- no
- id
- f9411057-33b7-4d8b-8046-bbc7f62256b5
- date added to LUP
- 2016-08-25 09:51:59
- date last changed
- 2024-03-07 11:04:24
@article{f9411057-33b7-4d8b-8046-bbc7f62256b5,
abstract = {{<p>Regenerative tissues such as the skin epidermis, the intestinal mucosa or the hematopoietic system are organized in a hierarchical manner with stem cells building the top of this hierarchy. Somatic stem cells harbor the highest self-renewal activity and generate a series of multipotent progenitors which differentiate into lineage committed progenitors and subsequently mature cells. In this report, we applied an in-depth quantitative proteomic approach to analyze and compare the full proteomes of ex vivo isolated and FACS-sorted populations highly enriched for either multipotent hematopoietic stem/progenitor cells (HSPCs, Lin(neg)Sca-1(+)c-Kit(+)) or myeloid committed precursors (Lin(neg)Sca-1(-)c-Kit(+)). By employing stable isotope dimethyl labeling and high-resolution mass spectrometry, more than 5000 proteins were quantified. From biological triplicate experiments subjected to rigorous statistical evaluation, 893 proteins were found differentially expressed between multipotent and myeloid committed cells. The differential protein content in these cell populations points to a distinct structural organization of the cytoskeleton including remodeling activity. In addition, we found a marked difference in the expression of metabolic enzymes, including a clear shift of specific protein isoforms of the glycolytic pathway. Proteins involved in translation showed a collective higher expression in myeloid progenitors, indicating an increased translational activity. Strikingly, the data uncover a unique signature related to immune defense mechanisms, centering on the RIG-I and type-1 interferon response systems, which are installed in multipotent progenitors but not evident in myeloid committed cells. This suggests that specific, and so far unrecognized, mechanisms protect these immature cells before they mature. In conclusion, this study indicates that the transition of hematopoietic stem/progenitors toward myeloid commitment is accompanied by a profound change in processing of cellular resources, adding novel insights into the molecular mechanisms at the interface between multipotency and lineage commitment.</p>}},
author = {{Klimmeck, Daniel and Hansson, Jenny and Raffel, Simon and Vakhrushev, Sergey Y and Trumpp, Andreas and Krijgsveld, Jeroen}},
issn = {{1535-9484}},
keywords = {{Animals; Cell Differentiation; Female; Flow Cytometry; Glycolysis; Hematopoiesis; Hematopoietic Stem Cells; Immunohistochemistry; Mice; Mice, Inbred C57BL; Multipotent Stem Cells; Myeloid Cells; Proteome; Proteomics; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry}},
language = {{eng}},
number = {{8}},
pages = {{286--302}},
publisher = {{American Society for Biochemistry and Molecular Biology}},
series = {{Molecular & Cellular Proteomics}},
title = {{Proteomic cornerstones of hematopoietic stem cell differentiation : distinct signatures of multipotent progenitors and myeloid committed cells}},
url = {{http://dx.doi.org/10.1074/mcp.M111.016790}},
doi = {{10.1074/mcp.M111.016790}},
volume = {{11}},
year = {{2012}},
}