Background and Future Considerations for Human Cord Blood Hematopoietic Cell Transplantation, Including Economic Concerns

Broxmeyer, Hal E.; Farag, Sherif

doi:10.1089/scd.2013.0382

Cited by 26 publications

(26 citation statements)

References 56 publications

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“…The limited numbers of HSCs that are present in single units of CB is still an obstacle for more widespread clinical use of CB for HCT 7,8 . To overcome this limitation, a number of efforts to expand HSCs in CB have been made 10–16 .…”

Section: Resultsmentioning

confidence: 99%

“…Allogeneic HSC transplantation is a life-saving treatment for malignant and non-malignant disorders 4,5 . HSCs isolated from umbilical cord blood (CB) are used for hematopoietic cell transplantation (HCT) 6–11 , but due to limited numbers of HSCs in single units of umbilical CB, a number of methods have been proposed for ex vivo expansion of human HSCs 7,8,12 . We show here that antagonism of the nuclear hormone receptor PPARγ promotes ex vivo expansion of phenotypically and functionally-defined subsets of human CB HSCs and hematopoietic progenitor cells (HSPCs).…”

mentioning

confidence: 99%

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Antagonism of PPAR-γ signaling expands human hematopoietic stem and progenitor cells by enhancing glycolysis

Guo

Huang

Lee³

et al. 2018

Nat Med

123

109

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Hematopoietic stem cells (HSCs) quiescently reside in bone marrow niches and have the capacity to self-renew or differentiate to form all blood cells throughout the lifespan of an animal1–3. Allogeneic HSC transplantation is a life-saving treatment for malignant and non-malignant disorders4,5. HSCs isolated from umbilical cord blood (CB) are used for hematopoietic cell transplantation (HCT)6–11, but due to limited numbers of HSCs in single units of umbilical CB, a number of methods have been proposed for ex vivo expansion of human HSCs7,8,12. We show here that antagonism of the nuclear hormone receptor PPARγ promotes ex vivo expansion of phenotypically and functionally-defined subsets of human CB HSCs and hematopoietic progenitor cells (HSPCs). PPARγ antagonism in CB HSPCs strongly downregulated expression of several differentiation associated genes, as well as fructose 1, 6-bisphosphatase (FBP1), a negative regulator of glycolysis, and enhanced glycolysis without compromising mitochondrial metabolism. The expansion of CB HSPCs by PPARγ antagonism was completely suppressed by removal of glucose or inhibition of glycolysis. Moreover, knockdown of FBP1 expression promoted glycolysis and ex vivo expansion of long-term repopulating CB HSPCs, whereas overexpression of FBP1 suppressed the expansion of CB HSPCs induced by PPARγ antagonism. Our study suggests the possibility for a new and simple means for metabolic reprogramming of CB HSPCs to improve the efficacy of HCT.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Antagonism of PPAR-γ signaling expands human hematopoietic stem and progenitor cells by enhancing glycolysis

Guo

Huang

Lee³

et al. 2018

Nat Med

123

109

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“…However, it is not yet clear whether or not PGE will be advantageous in context of a single CB HCT. This is important, because it is necessary to enhance single CB HCT, rather than that of double CB HCT, for economic reasons [59]. Of interest, is that in a mouse BM HCT context, the combined use of a DPP4 inhibitor and of PGE resulted in better engraftment than that of either a DPP4 inhibitor or PGE, each alone [60].…”

Section: Ongoing Experimental Laboratory and Clinical Efforts To Ementioning

confidence: 99%

“…Double CB HCT certainly served its purpose for increased numbers of CB HCT, but there is no apparent difference in times to engraftment with double compared to single CB HCT, both of which still lag behind the accelerated times to engraftment noted with BM- or mPB-HCT. The expense for two vs. one CB unit is usually twice the cost, and one way to decrease the cost, is to find a relatively inexpensive means to enhance single CB HCT [59]. As a means to find a way to increase the numbers of CB HSC/HPC for CB HCT, different groups have experimented with means to expand the numbers of these cells outside the body ( ex-vivo ).…”

Section: Ongoing Experimental Laboratory and Clinical Efforts To Ementioning

confidence: 99%

Enhancing the efficacy of engraftment of cord blood for hematopoietic cell transplantation

Broxmeyer

2016

Transfusion and Apheresis Science

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Clinical Cord Blood (CB) Hematopoietic Cell Transplantation (HCT) has progressed well since the initial successful CB HCT that saved the life of a young boy with Fanconi anemia. The recipient is alive and well now 28 years out since that first transplant with CB cells from his HLA-matched sister. CB HCT has now been used to treat over 35,000 patients with various malignant and non-malignant disorders mainly using HLA-matched or partially HLA-disparate allogeneic CB cells. There are advantages and disadvantages to using CB for HCT compared to other sources of transplantable hematopoietic stem (HSC) and progenitor (HPC) cells. One disadvantage of the use of CB as a source of transplantable HSC and HPC is the limited number of these cells in a single CB collected, and slower time to neutrophil, platelet and immune cell recovery. This review describes current attempts to: increase the collection of HSC/HPC from CB, enhance the homing of the infused cells, ex-vivo expand numbers of collected HSC/HPC and increase production of the infused CB cells that reach the marrow. The ultimate goal is to manipulate efficiency and efficacy for safe and economical use of single unit CB HCT.

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“…Three major sources of HSC for HCT are: BM, peripheral blood and CB [9,10]. Compared with the other sources, CB has advantages, including ready availability, less strict HLA matching requirements, lower incidence of graft vs. host disease and virus infection, and low probability of relapse among patients with minimal residual disease [11–13]. However, delayed hematopoietic recovery and immune reconstitution due to limited numbers of HSCs are major limiting factors preventing the wider use of HCT based cell therapy.…”

Section: Introductionmentioning

confidence: 99%

Enhancing human cord blood hematopoietic stem cell engraftment by targeting nuclear hormone receptors

Guo

Huang

Broxmeyer

2018

Current Opinion in Hematology

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Purpose of review Allogeneic hematopoietic cell transplantation (HCT) is a life-saving therapy for hematological and non-hematological diseases. Cord blood (CB) is a source of transplantable hematopoietic stem cells (HSCs), but limited numbers of HSCs in single CB units, which may cause delayed neutrophil, platelet, and immune cell reconstitution, is a major problem for efficient transplantation. Ex vivo expansion and enhanced homing of CB HSC may overcome this disadvantage and improve its long-term engraftment. Here, we discuss the role of nuclear hormone receptors (NRs) signaling in human CB HSC engraftment. Recent findings Antagonizing Retinoid acid receptor (RAR) signaling promotes human HSC expansion and increases myeloid cell production. CB CD34+ cells expanded by SR1 promotes efficient myeloid recovery after transplantation compared with control groups, and leads to successful engraftment. Short-term treatment of glucocorticoids enhances homing and long-term engraftment of human HSCs and HPCs in NSG mice. PPARγ antagonism expands human HSCs and HPCs by preventing differentiation and enhancing glucose metabolism. These findings demonstrate that NR signaling components might be promising targets for improving human CB HCT. Summary Better understanding of molecular mechanisms underlying human HSC expansion and homing mediated by NR signaling pathways will facilitate enhanced HCT efficacy.

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Background and Future Considerations for Human Cord Blood Hematopoietic Cell Transplantation, Including Economic Concerns

Cited by 26 publications

References 56 publications

Antagonism of PPAR-γ signaling expands human hematopoietic stem and progenitor cells by enhancing glycolysis

Antagonism of PPAR-γ signaling expands human hematopoietic stem and progenitor cells by enhancing glycolysis

Enhancing the efficacy of engraftment of cord blood for hematopoietic cell transplantation

Enhancing human cord blood hematopoietic stem cell engraftment by targeting nuclear hormone receptors

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