Evidence map›Paper›PMID 34620229›Full record

ArticleStem cell research & therapy2021

Longitudinal clonal tracking in humanized mice reveals sustained polyclonal repopulation of gene-modified human-HSPC despite vector integration bias.

Gajendra W Suryawanshi, Hubert Arokium, Sanggu Kim, Wannisa Khamaikawin, Samantha Lin, Saki Shimizu, Koollawat Chupradit, YooJin Lee, Yiming Xie, Xin Guan and 4 more

Open access · goldAbstract read
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In one paragraph

Article in Stem cell research & therapy, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact, top 90% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed, 2 citations in OpenAlex.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors at 4 institutions in 2 countries.

Gajendra W SuryawanshiDepartment of Microbiology, Immunology and Molecular Genetics, University of California, 615 Charles E. Young Dr. South, BSRB, Rm 173, Los Angeles, CA, 90095, USA.
Hubert ArokiumDepartment of Microbiology, Immunology and Molecular Genetics, University of California, 615 Charles E. Young Dr. South, BSRB, Rm 173, Los Angeles, CA, 90095, USA.
Sanggu KimDepartment of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, 43210, USA.
Wannisa KhamaikawinSchool of Nursing, University of California, Los Angeles, CA, 90095, USA.
Samantha LinSchool of Nursing, University of California, Los Angeles, CA, 90095, USA.
Saki ShimizuSchool of Nursing, University of California, Los Angeles, CA, 90095, USA.
Koollawat ChupraditSchool of Nursing, University of California, Los Angeles, CA, 90095, USA.
YooJin LeeDepartment of Microbiology, Immunology and Molecular Genetics, University of California, 615 Charles E. Young Dr. South, BSRB, Rm 173, Los Angeles, CA, 90095, USA.
Yiming XieDepartment of Microbiology, Immunology and Molecular Genetics, University of California, 615 Charles E. Young Dr. South, BSRB, Rm 173, Los Angeles, CA, 90095, USA.
Xin GuanDepartment of Microbiology, Immunology and Molecular Genetics, University of California, 615 Charles E. Young Dr. South, BSRB, Rm 173, Los Angeles, CA, 90095, USA.
Vasantika SuryawanshiDepartment of Molecular and Computational Biology, University of Southern California, Los Angeles, CA, 90089, USA.
Angela P PressonDivision of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, 84108, USA.
Dong-Sung AnUCLA AIDS Institute, Los Angeles, CA, 90095, USA.
Irvin S Y ChenDepartment of Microbiology, Immunology and Molecular Genetics, University of California, 615 Charles E. Young Dr. South, BSRB, Rm 173, Los Angeles, CA, 90095, USA. syuchen@mednet.ucla.edu.ORCID 0000-0003-1199-2415
University of California, Los Angeles · USBlack AIDS Institute · USThe Ohio State University · USUniversity of Southern California · US

Funding

Viral Immunology CoreU19AI117941 · NIAID · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI SYMONDS, GEOFFREY · 2015 to 2019
$10.6M
In Vivo Gene Editing for HIV-1 CureR01AI145038 · NIAID · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI CHEN, IRVIN S.Y. · 2019 to 2023
$3.4M
On-site, high-fidelity target sequencing and absolute quantitation for HIV-1 surveillanceR01HG010318 · NHGRI · OHIO STATE UNIVERSITY · PI KIM, SANGGU · 2018 to 2021
$2.9M
Hematopoietic stem/progenitor cell reservoirsR01AI110297 · NIAID · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI CHEN, IRVIN S.Y. · 2014 to 2018
$1.9M
Survival of the fittest HSPC repopulating clones by anti-HIV-1 gene-modificationR01HL125030 · NHLBI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI CHEN, IRVIN S.Y. · 2014 to 2017
$1.5M
Defining a therapeutic threshold in HSPC gene therapy for HIV-1 diseaseR00HL116234 · NHLBI · OHIO STATE UNIVERSITY · PI KIM, SANGGU · 2016 to 2018
$747k
High-accuracy, long-range sequencing for HIV-1 genotypingR21HG010108 · NHGRI · OHIO STATE UNIVERSITY · PI KIM, SANGGU · 2018 to 2020
$624k
Mouse and mathematical models for HIV-1 suppression through HSPCR56HL126544 · NHLBI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI CHEN, IRVIN S.Y., CHOU, TOM · 2014 to 2014
$381k
Defining a therapeutic threshold in HSPC gene therapy for HIV-1 diseaseK99HL116234 · NHLBI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI KIM, SANGGU · 2012 to 2013
$178k
NHGRI NIH HHS R01 HG010318NHGRI NIH HHS R21 HG010108NHLBI NIH HHS K99 HL116234NHLBI NIH HHS R00 HL116234NHLBI NIH HHS R01 HL125030NHLBI NIH HHS R56 HL126544NIAID NIH HHS R01 AI110297NIAID NIH HHS R01 AI145038NIAID NIH HHS U19 AI117941NIH HHS 5U19AI117941NIH HHS AI110297NIH HHS AI145038NIH HHS HL125030NIH HHS HL126544
6 · The paper itself

Abstract

backgroundCurrent understanding of hematopoiesis is largely derived from mouse models that are physiologically distant from humans. Humanized mice provide the most physiologically relevant small animal model to study human diseases, most notably preclinical gene therapy studies. However, the clonal repopulation dynamics of human hematopoietic stem and progenitor cells (HSPC) in these animal models is only partially understood. Using a new clonal tracking methodology designed for small sample volumes, we aim to reveal the underlying clonal dynamics of human cell repopulation in a mouse environment.

methodsHumanized bone marrow-liver-thymus (hu-BLT) mice were generated by transplanting lentiviral vector-transduced human fetal liver HSPC (FL-HSPC) in NOD.Cg-Prkdc

resultsA total of 897 HSPC clones were longitudinally tracked in hu-BLT mice-providing a first-ever demonstration of clonal dynamics and coordinated expansion of therapeutic and control vector-modified human cell populations simultaneously repopulating in the same humanized mice. The polyclonal repopulation stabilized at 19 weeks post-transplant and the contribution of the largest clone doubled within 4 weeks. Moreover, 550 (~ 60%) clones persisted over 6 weeks and were highly shared between different organs. The normal clonal profiles confirmed the safety of our gene therapy vectors. Multi-omics analysis of human FL-HSPC revealed that 54% of vector integrations in repopulating clones occurred within ± 1 kb of H3K36me3-enriched regions.

conclusionsHuman repopulation in mice is polyclonal and stabilizes more rapidly than that previously observed in humans. VIS preference for H3K36me3 has no apparent negative effects on HSPC repopulation. Our study provides a methodology to longitudinally track clonal repopulation in small animal models extensively used for stem cell and gene therapy research and with lentiviral vectors designed for clinical applications. Results of this study provide a framework for understanding the clonal behavior of human HPSC repopulating in a mouse environment, critical for translating results from humanized mice models to the human settings.

Indexed as

Hematopoietic Stem CellsHematopoietic Stem Cell TransplantationAnimalsDisease Models, AnimalHematopoiesisHumansMiceMice, Inbred NODMice, SCIDClonal dynamicsGene therapyHSPCHumanized mouseLoVIS-SeqMDAVIS tracking

Identifiers

PMID34620229
PMCPMC8499514
OpenAlexW3204198426

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.