Can anyone figure out some examples about TGF- in hematopoietic disease? and any therapeutic avenues?
Paper instructions
Answer the question. There is a 300-word cap on this part( must bee 300 or less words); references and question do not count toward this word limit.
In vitro, TGF-β is one of the most effective inhibitors of hematopoietic stem cell (HSC) proliferation. TGF-β has been proposed to be a fundamental regulator of HSC quiescence, sustaining a slow-cycling state of HSCs in vivo, due to their inherently quiescent state. In vitro neutralization of TGF-β was demonstrated to wake up early hematopoietic progenitor cells, confirming this theory. Changes in cytokine receptor expression and up-regulation of cyclin-dependent kinase inhibitors such as p15, p21, and p27 have been hypothesized as molecular pathways for TGF-β mediated growth suppression.
TGF-β, on the other hand, has been proven to suppress cell proliferation independently of p21 and p27. Additionally, neutralization of TGF-β coupled with antisense knockdown of p27 was shown to result in synergistically increased retroviral gene transfer efficiency in human CD34+ bone marrow (BM) cells, implying that TGF-β and p27 work in separate pathways.
In human CD34+ cells, TGF-β-mediated cell-cycle arrest has been suggested to occur through up-regulation of p57, another kind of inhibitor. This finding was further corroborated by the observation that p57 was highly enriched in mouse CD34−Kit+lineage−Sca1+ (CD34−KLS) cells as opposed to the more mature CD34+KLS fraction.
A high level of p57 was shown to correlate with the activation status of Smad2 and Smad3, which were reported to be uniquely phosphorylated in freshly isolated CD34−KLS cells but not in CD34+KLS progenitors. In addition, TGF-β was shown to up-regulate p57 in CD34−KLS cells in vitro. These findings hint to a mechanism in which TGF- induces p57 within the most basic HSC compartment, keeping them in a quiescent condition in vivo.
Question for discussion:
Can anyone figure out some examples about TGF- in hematopoietic disease? and any therapeutic avenues?
here is some references and materials I found:
Wang, B., Wang, Y., Chen, H. et al. Inhibition of TGFβ improves hematopoietic stem cell niche and ameliorates cancer-related anemia. Stem Cell Res Ther 12, 65 (2021). https://doi.org/10.1186/s13287-020-02120-9
Ulrika Blank, Stefan Karlsson; TGF-β signaling in the control of hematopoietic stem cells. Blood 2015; 125 (23): 3542–3550. doi: https://doi.org/10.1182/blood-2014-12-618090
Blank, U., Karlsson, S. The role of Smad signaling in hematopoiesis and translational hematology. Leukemia 25, 1379–1388 (2011). https://doi.org/10.1038/leu.2011.95
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