Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock

Mantel, Charlie; O’Leary, Heather A.; Chitteti, Brahmananda R.; Huang, Xinxin; Cooper, Scott; Hangoc, Giao; Brustovetsky, Nickolay; Srour, Edward F.; Lee, Man Ryul; Messina-Graham, Steven; Haas, David M.; Falah, Nadia; Kapur, Reuben; Pelus, Louis M.; Bardeesy, Nabeel; Fitamant, Julien; Ivan, Mircea; Kim, Kye Seong; Broxmeyer, Hal E.

doi:10.1016/j.cell.2015.04.054

Cited by 264 publications

(295 citation statements)

References 79 publications

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“…16 Takubo et al 4 found a defect in HSC self-renewal upon Hif-1a deletion and suggested that Hif-1a is an important mediator of HSC functions. Here we set out to acutely induce deletion of Hif-1a in the hematopoietic system and determine its short-and long-term impact on HSC maintenance.…”

Section: Resultsmentioning

confidence: 99%

Adult hematopoietic stem cells lacking Hif-1α self-renew normally

Vukovic

Sepúlveda

Subramani

et al. 2016

Blood

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Key Points• Hif-1a is dispensable for cellautonomous HSC survival. • HSCs do not require intrinsicHif-1a to respond to hematopoietic injury.The hematopoietic stem cell (HSC) pool is maintained under hypoxic conditions within the bone marrow microenvironment. Cellular responses to hypoxia are largely mediated by the hypoxia-inducible factors, Hif-1 and Hif-2. The oxygen-regulated a subunits of Hif-1 and Hif-2 (namely, Hif-1a and Hif-2a) form dimers with their stably expressed b subunits and control the transcription of downstream hypoxia-responsive genes to facilitate adaptation to low oxygen tension. An initial study concluded that Hif-1a is essential for HSC maintenance, whereby Hif-1a-deficient HSCs lost their ability to self-renew in serial transplantation assays. In another study, we demonstrated that Hif-2a is dispensable for cell-autonomous HSC maintenance, both under steady-state conditions and following transplantation. Given these unexpected findings, we set out to revisit the role of Hif-1a in cell-autonomous HSC functions. Here we demonstrate that inducible acute deletion of Hif-1a has no impact on HSC survival. Notably, unstressed HSCs lacking Hif-1a efficiently self-renew and sustain long-term multilineage hematopoiesis upon serial transplantation. Finally, Hif-1a-deficient HSCs recover normally after hematopoietic injury induced by serial administration of 5-fluorouracil. We therefore conclude that despite the hypoxic nature of the bone marrow microenvironment, Hif-1a is dispensable for cell-autonomous HSC maintenance.

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Section: Resultsmentioning

confidence: 99%

Adult hematopoietic stem cells lacking Hif-1α self-renew normally

Vukovic

Sepúlveda

Subramani

et al. 2016

Blood

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“…Apoptosis inhibition might be feasible at different levels of the signaling cascade: (a) engagement of upstream protective pathways (i.e., cytokines); (b) inhibition of detrimental signals (i.e., ROS inhibition); or (c) modulation of Bcl-2 protein levels. In contrast, apoptosis inhibition on a more downstream level (i.e., caspase activation) might not be sufficient to ensure survival as noncaspasedependent forms of cell death could be engaged upon mitochondrial damage [159,160].…”

Section: Hematopoietic Stem Cell Transplantationmentioning

confidence: 99%

Bcl‐2 proteins in development, health, and disease of the hematopoietic system

et al. 2016

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Members of the Bcl‐2 protein family regulate cell fate decisions following a variety of developmental cues or stress signals, with the outcomes of cell death or survival, thus shaping multiple mammalian tissues. This review describes in detail how anti‐ and proapoptotic Bcl‐2 proteins contribute to the development and functioning of the fetal and adult hematopoietic systems and how they influence the generation and maintenance of different hematopoietic lineages. An overview on how stress signals such as genotoxic stress or inflammation can compromise blood cell production, partially by engaging the intrinsic apoptosis pathway, is presented. Finally, the review describes how Bcl‐2 protein deregulation—either leading to increased apoptosis resistance or excessive cell death—contributes to many hematological disorders, with specific focus on rare disorders of hematopoiesis and how this knowledge may be used therapeutically.

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“…A variety of studies have been conducted to investigate the influence of oxygen concentration on the function of HSCs. HSCs are distributed in the bone marrow and umbilical cord blood which possess a hypoxic environment, but the separation and culture of HSCs are usually performed in non-physiological conditions [44,45]. The exposure of bone marrow and umbilical cord blood to normoxia may induce the differentiation of HSC, and reduce the efficiency of HSC expansion, which is also known as extraphysiologic oxygen shock/stress (EPHOSS).…”

Section: Oxygen Concentrationmentioning

confidence: 99%

“…The exposure of bone marrow and umbilical cord blood to normoxia may induce the differentiation of HSC, and reduce the efficiency of HSC expansion, which is also known as extraphysiologic oxygen shock/stress (EPHOSS). In the harvest of HSCs, the addition of cyclosporine A may protect HSCs against EPHOSS, which increases the proliferation capability and transplantation efficiency of HSCs [45].…”

Section: Oxygen Concentrationmentioning

confidence: 99%

Application of Bioreactor in Stem Cell Culture

Zhang¹,

Wang²,

Pong³

et al. 2017

JBiSE

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Stem cells (SCs), the undifferentiated biological cells, have the infinite capacity to self-renew and the pluripotent ability to differentiate. SCs and their derived products offer great promise for biomedical applications such as cell therapy, tissue engineering, regenerative medicine and drug screening. However, the clinical applications of SCs require a large amount of SCs with high quality and the number of SCs from their tissue resources is very limited. Large-scale expansion is needed to generate homogeneous SCs with good biological characteristics for clinical application. This necessitates a bioreactor system to provide controllable and stable conditions for stem cell (SC) culture. Traditional methods of bioreactor for maintenance and expansion of cells rely on two-dimensional (2-D) culture techniques, leading to loss self-renewal ability and differentiation capacity upon long-term culture. New approaches for SC expansion with bioreactor employ three-dimensional (3-D) cell growth to mimic their environment in vivo. In this review, we summarize the application of bioreactors in SC culture.

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Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock

Cited by 264 publications

References 79 publications

Adult hematopoietic stem cells lacking Hif-1α self-renew normally

Adult hematopoietic stem cells lacking Hif-1α self-renew normally

Bcl‐2 proteins in development, health, and disease of the hematopoietic system

Application of Bioreactor in Stem Cell Culture

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