| 1. |
- Blank Savukinas, Ulrika, et al.
(författare)
-
Signaling pathways governing stem cell fate.
- 2008
-
Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 111:2, s. 492-503
-
Forskningsöversikt (refereegranskat)abstract
- Hematopoietic stem cells (HSCs) are historically the most thoroughly characterized type of adult stem cell, and the hematopoietic system has served as a principal model structure of stem-cell biology for several decades. However, paradoxically, although HSCs can be defined by function and even purified to near-homogeneity, the intricate molecular machinery and the signaling mechanisms regulating fate events, such as self-renewal and differentiation, have remained elusive. Recently, several developmentally conserved signaling pathways have emerged as important control devices of HSC fate, including Notch, Wingless-type (Wnt), Sonic hedgehog (Shh), and Smad pathways. HSCs reside in a complex environment in the bone marrow, providing a niche that optimally balances signals that control self-renewal and differentiation. These signaling circuits provide a valuable structure for our understanding of how HSC regulation occurs, concomitantly with providing information of how the bone marrow microenvironment couples and integrates extrinsic with intrinsic HSC fate determinants. It is the focus of this review to highlight some of the most recent developments concerning signaling pathways governing HSC fate.
|
|
| 2. |
- Blank Savukinas, Ulrika, et al.
(författare)
-
Smad7 promotes self-renewal of hematopoietic stem cells in vivo.
- 2006
-
Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 108:13, s. 4246-4254
-
Tidskriftsartikel (refereegranskat)abstract
- The Smad-signaling pathway downstream of the transforming growth factor–beta superfamily of ligands is an evolutionarily conserved signaling circuitry with critical functions in a wide variety of biologic processes. To investigate the role of this pathway in the regulation of hematopoietic stem cells (HSCs), we have blocked Smad signaling by retroviral gene transfer of the inhibitory Smad7 to murine HSCs. We report here that the self-renewal capacity of HSCs is promoted in vivo upon blocking of the entire Smad pathway, as shown by both primary and secondary bone marrow (BM) transplantations. Importantly, HSCs overexpressing Smad7 have an unperturbed differentiation capacity as evidenced by normal contribution to both lymphoid and myeloid cell lineages, suggesting that the Smad pathway regulates self-renewal independently of differentiation. Moreover, phosphorylation of Smads was inhibited in response to ligand stimulation in BM cells, thus verifying impairment of the Smad-signaling cascade in Smad7-overexpressing cells. Taken together, these data reveal an important and previously unappreciated role for the Smad-signaling pathway in the regulation of self-renewal of HSCs in vivo.
|
|
| 3. |
|
|
| 4. |
- Lopez de Lapuente Portilla, Aitzkoa, et al.
(författare)
-
Genome-wide association study on 13 167 individuals identifies regulators of blood CD34+cell levels
- 2022
-
Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 139:11, s. 1659-1669
-
Tidskriftsartikel (refereegranskat)abstract
- Stem cell transplantation is a cornerstone in the treatment of blood malignancies. The most common method to harvest stem cells for transplantation is by leukapheresis, requiring mobilization of CD34+ hematopoietic stem and progenitor cells (HSPCs) from the bone marrow into the blood. Identifying the genetic factors that control blood CD34+ cell levels could reveal new drug targets for HSPC mobilization. Here we report the first large-scale, genome-wide association study on blood CD34+ cell levels. Across 13 167 individuals, we identify 9 significant and 2 suggestive associations, accounted for by 8 loci (PPM1H, CXCR4, ENO1-RERE, ITGA9, ARHGAP45, CEBPA, TERT, and MYC). Notably, 4 of the identified associations map to CXCR4, showing that bona fide regulators of blood CD34+ cell levels can be identified through genetic variation. Further, the most significant association maps to PPM1H, encoding a serine/threonine phosphatase never previously implicated in HSPC biology. PPM1H is expressed in HSPCs, and the allele that confers higher blood CD34+ cell levels downregulates PPM1H. Through functional fine-mapping, we find that this downregulation is caused by the variant rs772557-A, which abrogates an MYB transcription factor–binding site in PPM1H intron 1 that is active in specific HSPC subpopulations, including hematopoietic stem cells, and interacts with the promoter by chromatin looping. Furthermore, PPM1H knockdown increases the proportion of CD34+ and CD34+90+ cells in cord blood assays. Our results provide the first large-scale analysis of the genetic architecture of blood CD34+ cell levels and warrant further investigation of PPM1H as a potential inhibition target for stem cell mobilization.
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
- Quere, Ronan, et al.
(författare)
-
SMAD4 binds HOXA9 in the cytoplasm and protects primitive hematopoietic cells against nuclear activation by HOXA9 and leukemia transformation.
- 2011
-
Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 117, s. 5918-5930
-
Tidskriftsartikel (refereegranskat)abstract
- We studied leukemic stem cells (LSCs) in a Smad4(-/-) mouse model of acute myelogenous leukemia (AML) induced either by the HOXA9 gene or by the fusion oncogene NUP98-HOXA9. While HOXA9-SMAD4 complexes accumulate in the cytoplasm of normal hematopoietic stem- and progenitor cells (HSPCs) transduced with these oncogenes, there is no cytoplasmic accumulation of HOXA9 in Smad4(-/-) HSPCs and as a consequence increased levels of HOXA9 accumulate in the nucleus leading to increased immortalization in vitro. Loss of Smad4 accelerates the development of leukemia in vivo due to an increase in transformation of HSPCs. Therefore, the cytoplasmic binding of HOXA9 by SMAD4 is a mechanism to protect HOXA9-induced transformation of normal HSPCs. Since Smad4 is a potent tumor suppressor involved in growth control, we developed a strategy to modify the subcellular distribution of SMAD4. We successfully disrupted the interaction between HOXA9 and SMAD4 to activate the TGF-beta pathway and apoptosis, leading to a loss of LSCs. Together, these findings reveal a major role for Smad4 in the negative regulation of leukemia initiation and maintenance induced by HOXA9/NUP98-HOXA9 and provide strong evidence that antagonizing SMAD4 stabilization by these oncoproteins might be a promising novel therapeutic approach in leukemia.
|
|
| 9. |
|
|
| 10. |
- Rörby, Emma, et al.
(författare)
-
Human hematopoietic stem/progenitor cells overexpressing Smad4 exhibit impaired reconstitution potential in vivo.
- 2012
-
Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 120, s. 4343-4351
-
Tidskriftsartikel (refereegranskat)abstract
- Hematopoietic stem cells (HSCs) constitute a rare population of tissue-specific cells that can self-renew and differentiate into all lineages of the blood cell system. These properties are critical for tissue regeneration and clinical applications of HSCs. Cord blood is an easily accessible source of HSCs. However, the number of HSCs from one unit is too low to effectively transplant most adult patients, and expansion of HSCs in vitro has met with limited success due to incomplete knowledge regarding mechanisms regulating self-renewal. Members of the transforming growth factor-β (TGF-β) superfamily have been shown to regulate HSCs through the Smad signaling pathway, however, its role in human HSCs has remained relatively uncharted in vivo. Therefore, we asked whether enforced expression of the common-Smad, Smad4, could reveal a role for TGF-β in human hematopoietic stem/progenitor cells (HSPCs) from cord blood. Using a lentiviral overexpression approach, we demonstrate that Smad4 overexpression sensitizes HSPCs to TGF-β, resulting in growth arrest and apoptosis in vitro. This phenotype translates in vivo into reduced HSPC reconstitution capacity yet intact lineage distribution. This suggests that the Smad pathway regulates self-renewal independently of differentiation. These findings demonstrate that the Smad signaling circuitry negatively regulates the regeneration capacity of human HSPCs in vivo.
|
|
