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?
