Deconstructing the Complexity of TGFβ Signaling in Hematopoietic Stem Cells: Quiescence and Beyond

Hinge, Ashwini; Filippi, Marie–Dominique

doi:10.1007/s40778-016-0069-x

Cited by 19 publications

(17 citation statements)

References 82 publications

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“…Karlsson, 2015; Hinge and Filippi, 2016). For instance, TGF-β signaling regulates the selfrenewal and quiescence of HSCs; it can also determine a cell's fate and lineage differentiation.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

The role of myeloid-derived suppressor cells (MDSC) in the inflammaging process

Salminen

Kaarniranta

Kauppinen

2018

Ageing Research Reviews

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“…Karlsson, 2015; Hinge and Filippi, 2016). For instance, TGF-β signaling regulates the selfrenewal and quiescence of HSCs; it can also determine a cell's fate and lineage differentiation.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

The role of myeloid-derived suppressor cells (MDSC) in the inflammaging process

Salminen

Kaarniranta

Kauppinen

2018

Ageing Research Reviews

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“…Currently, it is not known if it is the activation of MDSCs that controls the functions of HSCs and the progenitors of myeloid and lymphoid lineages in the bone marrow. However, there is substantial evidence that factors secreted by MDSCs, e.g., TGF-β, and IL-10, are potent regulators of HSCs [ 105 , 106 ]. In particular, it has been claimed that aged HSCs were remarkably sensitive to TGF-β signaling.…”

Section: Introductionmentioning

confidence: 99%

Immunosenescence: the potential role of myeloid-derived suppressor cells (MDSC) in age-related immune deficiency

Salminen

Kaarniranta

Kauppinen

2019

Cell. Mol. Life Sci.

115

126

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The aging process is associated with chronic low-grade inflammation in both humans and rodents, commonly called inflammaging. At the same time, there is a gradual decline in the functional capacity of adaptive and innate immune systems, i.e., immunosenescence, a process not only linked to the aging process, but also encountered in several pathological conditions involving chronic inflammation. The hallmarks of immunosenescence include a decline in the numbers of naïve CD4 + and CD8 + T cells, an imbalance in the T cell subsets, and a decrease in T cell receptor (TCR) repertoire and signaling. Correspondingly, there is a decline in B cell lymphopoiesis and a reduction in antibody production. The age-related changes are not as profound in innate immunity as they are in adaptive immunity. However, there are distinct functional deficiencies in dendritic cells, natural killer cells, and monocytes/macrophages with aging. Interestingly, the immunosuppression induced by myeloid-derived suppressor cells (MDSC) in diverse inflammatory conditions also targets mainly the T and B cell compartments, i.e., inducing very similar alterations to those present in immunosenescence. Here, we will compare the immune profiles induced by immunosenescence and the MDSC-driven immunosuppression. Given that the appearance of MDSCs significantly increases with aging and MDSCs are the enhancers of other immunosuppressive cells, e.g., regulatory T cells (Tregs) and B cells (Bregs), it seems likely that MDSCs might remodel the immune system, thus preventing excessive inflammation with aging. We propose that MDSCs are potent inducers of immunosenescence.

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“…JNK is another downstream target of TGFβ which activates some apoptotic factors such as Bcl2, Bad. Therefore, inhibition of TGFβ pathway not only leads to P57, P38MAPK, and JNK inhibition which is associated with cell cycle promotion, but also inhibits the apoptotic pathways (42)(43)(44).…”

Section: Discussionmentioning

confidence: 99%

Combination of SB431542, Chir9901, and Bpv as a novel supplement in the culture of umbilical cord blood hematopoietic stem cells

Zarrabi

Afzal

Asghari

et al. 2020

Preprint

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Background: Small molecule compounds have been well recognized for their promising power in generation, expansion and maintenance of embryonic or adult stem cells. The aim of this study was to identify a novel combination of small molecules in order to optimize the ex vivo expansion of umbilical cord blood derived-CD34+ cells. Methods: Considering the most important signaling pathways involved in the self-renewal of hematopoietic stem cells, CB-CD34+ cells were expanded with cytokines in the presence of seven small molecules including SB, PD, Chir, Bpv, Pur, Pμ and NAM. Eliminativism approach was used to find the best combination of selected small molecules for effective ex vivo expansion of CD34+ cell. In each step, proliferation, self-renewal, and clonogenic potential of the expanded cells as well as expression of some hematopoietic stem cell related genes were studied. Finally, the engraftment potential of expanded cells was also examined by the mouse intra-uterine transplantation model. Results: Our data shows that simultaneous use of SB431542 (TGF-β inhibitor), Chir9901 (GSK3 inhibitor) and Bpv (PTEN inhibitor), resulted in a 50-fold increase in the number of CD34+CD38- cells. This was further reflected in approximately 3 times increase in clonogenic potential of the small molecule cocktail-expanded cells. These cells, also, showed a 1.5-fold higher engraftment potential in the peripheral blood of NMRI model of in utero transplantation. These results are in total conformity with up-regulation of HOXB4, GATA2 and CD34 marker gene as well as CXCR4 homing gene. Conclusion: Taken together, our findings introduce a novel combination of small molecules to improve the yield of existing protocols used in the expansion of hematopoietic stem cells.

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Deconstructing the Complexity of TGFβ Signaling in Hematopoietic Stem Cells: Quiescence and Beyond

Cited by 19 publications

References 82 publications

The role of myeloid-derived suppressor cells (MDSC) in the inflammaging process

The role of myeloid-derived suppressor cells (MDSC) in the inflammaging process

Immunosenescence: the potential role of myeloid-derived suppressor cells (MDSC) in age-related immune deficiency

Combination of SB431542, Chir9901, and Bpv as a novel supplement in the culture of umbilical cord blood hematopoietic stem cells

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