Past, present, and future efforts to enhance the efficacy of cord blood hematopoietic cell transplantation

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Abstract

Cord blood (CB) has been used as a viable source of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) in over 35,000 clinical hematopoietic cell transplantation (HCT) efforts to treat the same variety of malignant and non-malignant disorders treated by bone marrow (BM) and mobilized peripheral blood (mPB) using HLA-matched or partially HLA-disparate related or unrelated donor cells for adult and children recipients. This review documents the beginning of this clinical effort that started in the 1980’s, the pros and cons of CB HCT compared to BM and mPB HCT, and recent experimental and clinical efforts to enhance the efficacy of CB HCT. These efforts include means for increasing HSC numbers in single CB collections, expanding functional HSCs ex vivo, and improving CB HSC homing and engraftment, all with the goal of clinical translation. Concluding remarks highlight the need for phase I/II clinical trials to test the experimental procedures that are described, either alone or in combination.

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Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells.

Anthony Boitano, Jian Wang, Russell D. Romeo … (2010)

Although practiced clinically for more than 40 years, the use of hematopoietic stem cell (HSC) transplants remains limited by the ability to expand these cells ex vivo. An unbiased screen with primary human HSCs identified a purine derivative, StemRegenin 1 (SR1), that promotes the ex vivo expansion of CD34+ cells. Culture of HSCs with SR1 led to a 50-fold increase in cells expressing CD34 and a 17-fold increase in cells that retain the ability to engraft immunodeficient mice. Mechanistic studies show that SR1 acts by antagonizing the aryl hydrocarbon receptor (AHR). The identification of SR1 and AHR modulation as a means to induce ex vivo HSC expansion should facilitate the clinical use of HSC therapy.

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HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention.

X-J. Yang, E Seto (2007)

Acetylation of the epsilon-amino group of a lysine residue was first discovered with histones in 1968, but the responsible enzymes, histone acetyltransferases and deacetylases, were not identified until the mid-1990s. In the past decade, knowledge about this modification has exploded, with targets rapidly expanding from histones to transcription factors and other nuclear proteins, and then to cytoskeleton, metabolic enzymes, and signaling regulators in the cytoplasm. Thus, protein lysine acetylation has emerged as a major post-translational modification to rival phosphorylation. In this issue of Oncogene, 19 articles review various aspects of the enzymes governing lysine acetylation, especially about their intimate links to cancer. To introduce the articles, we highlight here four central themes: (i) multisubunit enzymatic complexes; (ii) non-histone substrates in diverse cellular processes; (iii) interplay of lysine acetylation with other regulatory mechanisms, such as noncoding RNA-mediated gene silencing and activation; and (iv) novel therapeutic strategies and preventive measures to combat cancer and other human diseases.

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Regulation of the HIF-1alpha level is essential for hematopoietic stem cells.

Keiyo Takubo, Nobuhito Goda, Wakako Yamada … (2010)

Hematopoietic stem cells (HSCs) are sustained in a specific microenvironment known as the stem cell niche. Mammalian HSCs are kept quiescent in the endosteal niche, a hypoxic zone of the bone marrow (BM). In this study, we show that normal HSCs maintain intracellular hypoxia and stabilize hypoxia-inducible factor-1alpha (HIF-1alpha) protein. In HIF-1alpha-deficient mice, the HSCs lost their cell cycle quiescence and HSC numbers decreased during various stress settings including bone marrow transplantation, myelosuppression, or aging, in a p16(Ink4a)/p19(Arf)-dependent manner. Overstabilization of HIF-1alpha by biallelic loss of an E3 ubiquitin ligase for HIF-1alpha (VHL) induced cell cycle quiescence in HSCs and their progenitors but resulted in an impairment in transplantation capacity. In contrast, monoallelic loss of VHL induced cell cycle quiescence and improved BM engraftment during bone marrow transplantation. These data indicate that HSCs maintain cell cycle quiescence through the precise regulation of HIF-1alpha levels. Copyright 2010 Elsevier Inc. All rights reserved.

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Author and article information

Contributors

Xinxin Huang: Role: ConceptualizationRole: Writing – Original Draft PreparationRole: Writing – Review & Editing

Bin Guo: Role: ConceptualizationRole: Writing – Original Draft PreparationRole: Writing – Review & Editing

Maegan Capitano: Role: ConceptualizationRole: Writing – Original Draft PreparationRole: Writing – Review & Editing

Hal E. Broxmeyer: Role: ConceptualizationRole: Writing – Original Draft PreparationRole: Writing – Review & Editing

ORCID: https://orcid.org/0000-0001-6575-0476

Journal

Journal ID (nlm-ta): F1000Res

Journal ID (iso-abbrev): F1000Res

Journal ID (pmc): F1000Research

Title: F1000Research

Publisher: F1000 Research Limited (London, UK )

ISSN (Electronic): 2046-1402

Publication date (Electronic): 31 October 2019

Publication date Collection: 2019

Volume: 8

Electronic Location Identifier: F1000 Faculty Rev-1833

Affiliations

[1 ]Xuhui Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China

[2 ]Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China

[3 ]Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, 46202-5181, USA

Author notes

[a ] hbroxmey@ 123456iupui.edu

[#]

These authors contributed equally to this review and all are considered co-first authors

Competing interests: HEB was a member of the Medical Scientific Advisory Board of Cord:Use, a cord blood banking company up until 2018. Cord:Use provided cord blood samples for some of the papers from the Broxmeyer Laboratory but had no input into the use of the cord blood samples provided, for any of the work performed, or for anything in the papers published. HEB started in October 2019 as a member of the Scientific Advisory Board of Elixell, a cell therapy company. Elixell had no input into any of the studies shown or in the writing of this review. The other authors have no competing interests to declare.

Author information

Hal E. Broxmeyer https://orcid.org/0000-0001-6575-0476

Article

DOI: 10.12688/f1000research.20002.1

PMC ID: 6823900

SO-VID: 7b6f9b38-5425-4f25-abf9-ef8a5619b44a

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This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date accepted : 23 October 2019

Funding

Funded by: NIH/NHLBI

Award ID: R35HL139599

Funded by: NIH/NIDDK

Award ID: R01DK109188

Funded by: NIH/NIDDK

Award ID: U54DK106846

The studies reported in this review from the Broxmeyer laboratory were supported by the following US Public Health Service grants to Dr. Broxmeyer: R35 HL139599, R01 DK109188, and U54 DK106846.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Past, present, and future efforts to enhance the efficacy of cord blood hematopoietic cell transplantation

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Most cited references 115

Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells.

HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention.

Regulation of the HIF-1alpha level is essential for hematopoietic stem cells.

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