Notch signals are required for in vitro but not in vivo maintenance of human hematopoietic stem cells and delay the appearance of multipotent progenitors

Benveniste, Patricia; Serra, Pablo Catalán; Dervovic, Dzana; Herer, Elaine; Knowles, Gisele; Mohtashami, Mahmood; Zúñiga‐Pflücker, Juan Carlos

doi:10.1182/blood-2013-07-505099

Cited by 40 publications

(41 citation statements)

References 38 publications

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“…Latest findings support the fact that Notch signals maintain human HSCs in vitro such that they preserve their hematopoietic-reconstituting ability in vivo delaying the appearance of two newly described early progenitor cells. Interestingly, Notch signaling was shown not to be required for self-renewal of human HSC in vivo by Benveniste et al [15]. Clinically relevant effects in terms of reduction in TRM, graft failure rates and increase in overall survival (OS) rates are encouraging.…”

Section: Notch Signaling Pathwaymentioning

confidence: 88%

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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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Section: Notch Signaling Pathwaymentioning

confidence: 88%

“…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%

Modalities to Improve Cord Blood Engraftment

Yurdakul¹

2014

J Stem Cell Res Ther

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“…Because species differences exist, studies in human are of critical translational importance. Indeed, previous work from our laboratory and others, although mostly limited to pan-Notch activation and inhibition experiments, confirmed certain roles for Notch activation in early hematopoietic lineage decisions (15)(16)(17)(18), but also revealed some subtle differences during intrathymic stages of T cell development (16,(19)(20)(21)(22). In more recent work, we revealed a critical role for Jagged2-mediated Notch3 activation in human TCR-gd T cell development (23), a mechanism that seems absent in mouse (24,25).…”

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confidence: 89%

Notch3 Activation Is Sufficient but Not Required for Inducing Human T-Lineage Specification

Waegemans

Walle

Medts

et al. 2014

The Journal of Immunology

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Although the role for the individual Notch receptors in early hematopoiesis have been thoroughly investigated in mouse, studies in human have been mostly limited to the use of pan-Notch inhibitors. However, such studies in human are important to predict potential side effects of specific Notch receptor blocking reagents because these are currently being considered as therapeutic tools to treat various Notch-dependent diseases. In this study, we studied the individual roles of Notch1 and Notch3 in early human hematopoietic lineage decisions, particularly during T-lineage specification. Although this process in mice is solely dependent on Notch1 activation, we recently reported Notch3 expression in human uncommitted thymocytes, raising the possibility that Notch3 mediates human T-lineage specification. Although expression of a constitutive activated form of Notch3 (ICN3) results in the induction of T-lineage specification in human CD34+ hematopoietic progenitor cells, similar to ICN1 overexpression, loss-of-function studies using blocking Abs reveal that only Notch1, but not Notch3, is critical in this process. Blocking of Notch1 activation in OP9-DLL4 cocultures resulted in a complete block in T-lineage specification and induced monocytic and plasmacytoid dendritic cell differentiation instead. In fetal thymus organ cultures, impeded Notch1 activation resulted in B and dendritic cell development. In contrast, Notch3 blocking Abs only marginally affected T-lineage specification and hematopoietic differentiation with a slight increase in monocyte development. No induction of B or dendritic cell development was observed. Thus, our results unambiguously reveal a nonredundant role for Notch1 in human T-lineage specification, despite the expression of other Notch receptors.

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“…We fou AMD3100 gro cells were dete cells were dete upress.com milar in morpho CXCR4 and c-k g Western blott 00 group comp kidney [12] , mo eason why the C D3100 increas on in renal tissu ive cells were 3 also found th up. [26,27] Vol. also examined whether CXCR4 receptor antagonism ameliorates the loss of renal function following I/R [28] .…”

Section: Amd3 Kidneysmentioning

confidence: 99%

CXC-chemokine receptor 4 antagonist prevents acute kidney injury potentially through recruiting bone marrow-derived stem cells

Guo

Chen

Gao

et al. 2015

JBEI

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Background: Existing literature suggests that stromal-cell derived factor 1 (SDF-1) interacts with CXC-chemokine receptor 4 (CXCR4) in regulating the homing of stem cells derived from bone marrow. The CXCR4 antagonist, AMD3100, disrupts this SDF-1/CXCR4 interaction and triggers stem cell mobilization. We investigated whether AMD3100 could ameliorate renal ischemia reperfusion (I/R) injury via recruiting circulating stem cells to injured kidneys. Methods:We divided Sprague-Dawley rats into four groups, Sham, Sham + AMD3100, I/R, and I/R + AMD3100. All groups were treated with single subcutaneous injections of AMD3100 (5 mg/kg) or saline after sham surgery or I/R injury. Serum and renal tissues were harvested 12 hours and 3 days after treatment. We assessed survival, renal function changes, and histopathological alterations. TUNEL staining and caspase-3 expression levels were harnessed to measure tubular cell apoptosis, and circulating CXCR4 and CD34 positive mononuclear cells were identified by flow cytometry. Results:The I/R + AMD3100 group displayed significantly higher survival, lower serum creatinine, less prominent renal damage upon histopathological examination, and a lower degree of apoptosis than the I/R group. In addition, the AMD3100 treated group showed a significantly higher degree of CXCR4 and CD34 positive cell mobilization in the circulation and increased recruitment of these cells into the injured kidneys.Conclusions: AMD3100 promotes bone marrow stem cell mobilization and improves the recovery of renal function after I/R injury, and this effect may offer a promising therapeutic approach for acute kidney injury.

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Notch signals are required for in vitro but not in vivo maintenance of human hematopoietic stem cells and delay the appearance of multipotent progenitors

Abstract: Key Points Notch signals expand human HSC (CD90low) cells in vitro and delay the expansion of CD45RAint and CD45RAhi cells in vitro. HSCs expanded in vitro are equal to ex vivo CD90low cells in immune reconstitution.

Cited by 40 publications

References 38 publications

Modalities to Improve Cord Blood Engraftment

Modalities to Improve Cord Blood Engraftment

Notch3 Activation Is Sufficient but Not Required for Inducing Human T-Lineage Specification

CXC-chemokine receptor 4 antagonist prevents acute kidney injury potentially through recruiting bone marrow-derived stem cells

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