Blood stem cell fate regulation by Delta-1–mediated rewiring of IL-6 paracrine signaling

Csaszar, Elizabeth; Wang, Weijia; Usenko, Tatiana; Qiao, Wenlian; Delaney, Colleen; Bernstein, Irwin D.; Zandstra, Peter W.

doi:10.1182/blood-2013-08-520445

Cited by 22 publications

(22 citation statements)

References 34 publications

(45 reference statements)

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“…To understand the mechanism by which IL-1β affected KN6 cellularity, we analyzed the levels of IL-6, an inflammatory cytokine induced by IL-1β. IL-6 has been shown to inhibit the expansion of hematopoietic stem cells, in a manner which is blocked by Notch signaling 36 , bringing up the possibility that a similar mechanism could be at play in KN6/MEF co-cultures. Indeed, we found that any culture supplemented with IL-1β also contained high amounts of IL-6 protein, as assessed by ELISA.…”

Section: Resultsmentioning

confidence: 99%

Integration of T‐cell receptor, Notch and cytokine signals programs mouse γδ T‐cell effector differentiation

Zarin

Chen

et al. 2018

Immunol Cell Biol

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γδ T-cells perform a wide range of tissue and disease specific functions that are dependent on the effector cytokines produced by these cells. However, the aggregate signals required for the development of interferon-γ (IFNγ) and interleukin-17 (IL-17) producing γδ T-cells remain unknown. Here, we define the cues involved in the functional programming of γδ T-cells, by examining the roles of T-cell receptor (TCR), Notch, and cytokine-receptor signaling. KN6 γδTCR-transduced Rag2−/− T-cell progenitors were cultured on stromal cells variably expressing TCR and Notch ligands, supplemented with different cytokines. We found that distinct combinations of these signals are required to program IFNγ versus IL-17 producing γδ T cell subsets, with Notch and weak TCR ligands optimally enabling development of γδ17 cells in the presence of IL-1β, IL-21 and IL-23. Notably, these cytokines were also shown to be required for the intrathymic development of γδ17 cells. Together, this work provides a framework of how signals downstream of TCR, Notch and cytokine receptors integrate to program the effector function of IFNγ and IL-17 producing γδ T-cell subsets.

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Section: Resultsmentioning

confidence: 99%

Integration of T‐cell receptor, Notch and cytokine signals programs mouse γδ T‐cell effector differentiation

Zarin

Chen

et al. 2018

Immunol Cell Biol

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“…It is important to define and optimize culture conditions to maintain LTR cells. Ensuring the presence of clinically relevant HPC/mature cells in the UCB graft is stressed by Csaszar et al [14]. The authors suggested that, a 15 fold expansion of LTR HSC would enable patients up to 162 kg to receive a recommended cell dose of an unmanipulated unit if the HSC that are important for long term engraftment are present.…”

Section: Conclusion and Final Remarksmentioning

confidence: 99%

“…A novel way of Notch ligand Delta 1 mediated expansion via IL-6 induction was recently described by Csaszar E and colleagues [14]. They describe the way Delta 1 alters cytokine receptor distributions on hematopoietic cells, altering feedback networks and their impact on stem cell fate.…”

Section: Notch Signaling Pathwaymentioning

confidence: 99%

“…Clinically relevant effects in terms of reduction in TRM, graft failure rates and increase in overall survival (OS) rates are encouraging. The data received so far suggest a significant role of Notch signaling in HSC expansion to be used for UCBT [14,15].…”

Section: Notch Signaling Pathwaymentioning

confidence: 99%

“…Although decrease in relapse rates are reported, reaching adequate cell doses and the median neutrophil and platelet recovery time is still far from optimal [10,14]. One of the major advantages of dUCBT is that it maintains the platform to test novel expansion techniques.…”

Section: Double Ucbtmentioning

confidence: 99%

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Modalities to Improve Cord Blood Engraftment

Yurdakul¹

2014

J Stem Cell Res Ther

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Umblical cord blood (UCB) is one of the major sources of Hematopoietic Stem Cell Transplantation (HSCT) with increasing use in clinical practice. UCB can be a life saver for patients who do not have a matched unrelated adult donor or for patients who are in need of an urgent transplantation. Various factors make UCB a significant source of Hematopoietic Stem Cells (HSCs), including ease of procurement and lack of donor attrition, with the ability to process and long term storage of donor cells. Importantly, UCB donations can be used right away without the need for a "perfect" HLA match, thereby increasing donor access to HSCT, particularly for minority and mixed ethnicity patients, for whom a suitably matched related or unrelated donor may be difficult to locate. The major limitation of UCB is the quantity of cells to be infused. Although high proliferative potential allows one log less use of HSCs (HSC<10 5 /kg) compared to bone marrow (BM) or peripheral blood mononuclear cells (PBSC), even this amount cannot be reached in the majority of patients under donor search. When total nucleated cell (TNC) and CD34+ cell doses in UCB grafts are analyzed, a high correlation is observed with the rate of neutrophil and platelet engraftment, the incidence of graft failure and early transplant-related complications. It has been shown that UCB grafts with more than 3/6 HLA mismatches and with cell doses under the defined minimum threshold lead to higher transplantation related mortality (TRM). Especially when adult cord blood transplantation (UCBT) is the subject, providing units with enough cells remains the major drawback.Despite certain efforts, there is still an unmet need for increasing HSC cell dose and/or stimulating engraftment without loss of their long term repopulating (LTR) potential and reducing graft versus host disease (GVHD). Intrinsic and extrinsic cellular factors have been proven to act roles in HSC expansion thus justifying their role in in vitro and ex vivo culture conditions. Attempts to regulate these factors through ex vivo expansion methods aim to overcome insufficient cell numbers while methods promoting HSC homing is in favor of the latter. Combination of both appear to work synergistically. Induction or adoptive transfer of UCB derived immune cells particularly Natural Killer (NK) cells and regulatory T cells (T reg) with or without cytokines are also effective approaches for gaining better engraftment levels after UCBT. All of these approaches have been denoted as "successful" in pre-clinical in vitro and animal studies. Many of them have also been tested in early/later phase clinical trials resulting in encouraging results. We aim to review the current knowledge on UCB expansion and engraftment enhancer methods, a very rapidly improving field particularly in the last decade.Eltrombopag enhanced expansion of HSC/HPC of human UCB in vivo and in vitro, and promoted multi-lineage hematopoiesis through the expansion of BM HSC/HPC of human UCB in vivo. A novel c-MPL agonist, a small molecule, ...

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IL6RA, Interleukin-6 Receptor Subunit Alpha

Garbers¹,

Rose–John²

2016

Encyclopedia of Signaling Molecules

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Blood stem cell fate regulation by Delta-1–mediated rewiring of IL-6 paracrine signaling

Abstract: Key Points The Notch ligand Delta-1 reduces membrane bound IL-6R expression, inhibiting IL-6 cis-signaling and the production of myeloid cells. Combined with a dynamically fed culture system that minimizes IL-6 trans-signaling, Delta-1 produces rapid and sustained HSC engraftment.

Cited by 22 publications

References 34 publications

Integration of T‐cell receptor, Notch and cytokine signals programs mouse γδ T‐cell effector differentiation

Integration of T‐cell receptor, Notch and cytokine signals programs mouse γδ T‐cell effector differentiation

Modalities to Improve Cord Blood Engraftment

IL6RA, Interleukin-6 Receptor Subunit Alpha

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