Pharmacological inhibition of AKT activity in human CD34+ cells enhances their ability to engraft immunodeficient mice

Chen, Sisi; Gao, Rui; Kobayashi, Michihiro; Yu, Hao; Yao, Chonghua; Kapur, Reuben; Yoder, Mervin C.; Liu, Yan

doi:10.1016/j.exphem.2016.09.003

Cited by 6 publications

(7 citation statements)

References 42 publications

(59 reference statements)

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“…These three closely regulated pathways play central role in regulating proliferation, apoptosis, differentiation, cell adhesion and metabolism [15][16][17][18] with both complementary and antagonistic cellcontext dependent effects in hematopoiesis [19]. Highly active Rap1 and Ras pathways trigger PI3K and activated PI3K-Akt signaling has been associated with HSC exhaustion and depletion [20][21][22] as well as thrombocytopenia [20], whereas silencing enhances cell engraftment [23]. This latter outcome is consistent with our results with SR11Ly versus UM171 reflecting the enhanced engraftment, of the former.…”

Section: Resultsmentioning

confidence: 99%

Brief Report: A Differential Transcriptomic Profile of Ex Vivo Expanded Adult Human Hematopoietic Stem Cells Empowers Them for Engraftment Better than Their Surface Phenotype

Psatha

Georgolopoulos

Phelps

et al. 2017

Stem Cells Translational Medicine

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Transplantation of small cord blood (CB) units, or of autologous ex vivo-genetically modified adult hematopoietic stem cells (HSC), face the common challenge of suboptimal HSC doses for infusion and impaired engraftment of the transplanted cells. Ex vivo expansion of HSCs, using either cellbased coculture approaches or especially small molecules have been successfully tested mainly in CB and in prolonged cultures. Here, we explored whether innovative combinations of small molecules can sufficiently, after short culture, expand adult HSCs while retaining their functionality in vivo. We found that 5-day cultured cells, in the presence of the small molecule combinations tested, achieved higher engraftment levels in NSG mice than both their uncultured and their cytokine only-cultured counterparts. Surprisingly, the engraftment levels were neither concordant to the numbers of phenotypically similar HSCs expanded under different small molecule combinations, nor explained by their distinct companion cells present. Transcriptomic comparative analysis of sorted, phenotypically similar, ex vivo generated HSCs transplanted in equal numbers, suggested that HSCs generated under expansion conditions that maintain low expression of the Rap1/Ras/ PI3K-AKT pathway exhibit a superior functional profile in vivo. STEM CELLS TRANSLATIONAL MEDI-CINE 2017;6:1852-1858 SIGNIFICANCE STATEMENTHere, we document that the engraftment potential of ex vivo expanded phenotypically similar hematopoietic stem cells (HSCs) is dictated by the specific expansion conditions rather than their surface phenotype. The results of our study have important implications for all investigators studying the ex vivo expansion of adult HSCs.

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Section: Resultsmentioning

confidence: 99%

Brief Report: A Differential Transcriptomic Profile of Ex Vivo Expanded Adult Human Hematopoietic Stem Cells Empowers Them for Engraftment Better than Their Surface Phenotype

Psatha

Georgolopoulos

Phelps

et al. 2017

Stem Cells Translational Medicine

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“…AKTi-1/2 promotes quiescence and enhances engraftment of human UCB CD34 + cells in immunodeficient mice. This study may facilitate clinical strategies that can enhance the engraftment of human UCB HSPCs [ 103 ]. Phosphatidylinositol ether lipid analogs (PIAs), SH-5 and SH-6, were as effective as LY294002 in decreasing the amount of the PKB phosphorylated forms and inhibited proliferation and sensitization of HL60 cells to chemotherapeutic agents in concentrations that did not affect proliferation of normal hematopoietic progenitors [ 104 ].…”

Section: Regulation Of Hsc Fate and Malignancymentioning

confidence: 99%

Regulation of Hematopoietic Stem Cell Fate and Malignancy

Cho

Lee

Yoon

et al. 2020

IJMS

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The regulation of hematopoietic stem cell (HSC) fate decision, whether they keep quiescence, self-renew, or differentiate into blood lineage cells, is critical for maintaining the immune system throughout one’s lifetime. As HSCs are exposed to age-related stress, they gradually lose their self-renewal and regenerative capacity. Recently, many reports have implicated signaling pathways in the regulation of HSC fate determination and malignancies under aging stress or pathophysiological conditions. In this review, we focus on the current understanding of signaling pathways that regulate HSC fate including quiescence, self-renewal, and differentiation during aging, and additionally introduce pharmacological approaches to rescue defects of HSC fate determination or hematopoietic malignancies by kinase signaling pathways.

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“…The clinical utility of sirolimus has been mainly in immunosuppression, reducing host immunity in the context of tissue transplantation, 10,50 and suppressing donor immune attack on host cells in the prevention of graft-versus-host disease. [13][14][15][16] Our current observations may help to extend sirolimus' therapeutic utility beyond immunosuppression, as sirolimus acted on HSPCs to stimulate c-Kit and downstream signals, leading to increased HSPC self-renewal and engraftment.…”

Section: Discussionmentioning

confidence: 99%

Sirolimus augments hematopoietic stem and progenitor cell regeneration following hematopoietic insults

Wang

Hollinger

et al. 2020

Stem Cells

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The role of mammalian target of rapamycin and its suppressor sirolimus in the regulation of hematopoietic stem and progenitor cells (HSPCs) is controversial. We show here that sirolimus enhanced regeneration of HSPCs in mice exposed to sublethal total body irradiation (TBI) and other regenerative stressors. Sorted Lin−CD150+ bone marrow cells from sirolimus-treated TBI mice had increased expression of c-Kit and other hematopoietic genes. HSPCs from sirolimus-treated TBI mice were functionally competent when tested by competitive engraftment in vivo. Postradiation regeneration of HSPCs in mice treated with sirolimus was accompanied by decreased γ-H2AX levels detected by flow cytometry and increased expression of DNA repair genes by quantitative polymerase chain reaction. Reduction of cell death and DNA damage post-radiation by sirolimus was associated with enhanced clearance of cellular reactive oxygen species (ROS) in HSPCs. Increased HSPC recovery with sirolimus was also observed in mice injected with hematoxic agents, busulfan and 5-fluorouracil. In contrast, sirolimus showed no effect on HSPCs in normal mice at steady state, but stimulated HSPC expansion in mice carrying the Wv mutation at the c-Kit locus. In human to mouse xenotransplantation, sirolimus enhanced engraftment of irradiated human CD34+ cells. In summary, our results are consistent with sirolimus' acceleration of HSPC recovery in response to hematopoietic stress, associated with reduced DNA damage and ROS. Sirolimus might have clinical application for the treatment and prevention of hematopoietic injury.

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Pharmacological inhibition of AKT activity in human CD34+ cells enhances their ability to engraft immunodeficient mice

Cited by 6 publications

References 42 publications

Brief Report: A Differential Transcriptomic Profile of Ex Vivo Expanded Adult Human Hematopoietic Stem Cells Empowers Them for Engraftment Better than Their Surface Phenotype

Brief Report: A Differential Transcriptomic Profile of Ex Vivo Expanded Adult Human Hematopoietic Stem Cells Empowers Them for Engraftment Better than Their Surface Phenotype

Regulation of Hematopoietic Stem Cell Fate and Malignancy

Sirolimus augments hematopoietic stem and progenitor cell regeneration following hematopoietic insults

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