Geographic clonal tracking in macaques provides insights into HSPC migration and differentiation

Wu, Chuanfeng; Espinoza, Diego A.; Koelle, Samson; Potter, E. Lake; Lu, Rong; Li, Brian; Yang, Di; Fan, Xing; Donahue, Robert E.; Dunbar, Cynthia E.

doi:10.1084/jem.20171341

Cited by 35 publications

(61 citation statements)

References 56 publications

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“…ZL34, along with another monkey, ZL40(Table S1), received CMV-suppressing cidofovir for 4 months to study the impact of CMV reactivation on immune reconstitution. With the exception of ZL34, all other animals, including ZL40 also receiving cidofovir on the same schedule, continue to show stable, highly polyclonal output from transduced HSPC with no evidence for genotoxicity or malignant clonal expansions at latest follow up(4 months - 70 months, median: 25 months), regardless of having received HSPC transduced with vectors containing either an internal EF1α promoter(n=3) or the LTR-embedded MSCV promoter(n= 7), as previously published 15-17 .…”

Section: Resultssupporting

confidence: 64%

“…%GFP expression in the circulating nRBCs was also very high, but dropped precipitously before euthanasia, potentially due to transgene silencing. Other barcoded animals did not show expansion of GFP+ cells of any lineage over time, with similar levels in all lineages other than delayed reconstitution of GFP+ T cells due to TBI effects on the thymus(Figure S1F and 15-17 ).…”

Section: Resultsmentioning

confidence: 87%

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Aberrant Clonal Hematopoiesis Following Lentiviral Transduction of HSPC in a Rhesus Macaque

Espinoza

Fan

Yang

et al. 2019

Preprint

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Lentiviral vectors (LV) have been used for the delivery of genes into hematopoietic stem and progenitor cells (HSPC) in clinical trials worldwide. LV, in contrast to retroviral vectors, have not been associated with insertion site-associated malignant clonal expansions, and thus have been considered safer. Here, however, we present a case of markedly abnormal dysplastic clonal hematopoiesis impacting the erythroid, myeloid and megakaryocytic lineages in a rhesus macaque transplanted with HSPCs that were transduced with a LV containing a strong retroviral murine stem cell virus (MSCV) constitutive promoter-enhancer in the LTR. 9 insertions were mapped in the abnormal clone, resulting in overexpression and aberrant splicing of several genes of interest, including the cytokine stem cell factor and the transcription factor PLAG1. This case represents the first clear link between a lentiviral insertion-induced clonal expansion and a clinically abnormal transformed phenotype following transduction of normal primate or human HSPC, and are thus concerning, and suggest that strong constitutive promoters should not be included within LV vectors.

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Section: Resultssupporting

confidence: 64%

Section: Resultsmentioning

confidence: 87%

Aberrant Clonal Hematopoiesis Following Lentiviral Transduction of HSPC in a Rhesus Macaque

Espinoza

Fan

Yang

et al. 2019

Preprint

Self Cite

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“…6). In the control group, as reported before 66 , the chimerism at 4 months after transplantation was increased compared to one month post-transplantation and the number of barcodes detected in HSCs was lower than at the early timepoints after transplantation (Fig. 6c-d and 1b-d).…”

Section: Contribution Of Biased Hscs To the DC And Mkp Lineage After supporting

confidence: 76%

Erythropoietin directly remodels the clonal composition of murine hematopoietic multipotent progenitor cells

Eisele

Cosgrove

Magniez

et al. 2020

Preprint

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The cytokine erythropoietin (EPO) is a potent inducer of erythrocyte development and one of the most prescribed biopharmaceuticals. The action of EPO on erythroid progenitor cells is well established, but its action on hematopoietic stem cells (HSCs) is still debated. Here, using cellular barcoding, we traced the differentiation of hundreds of single HSCs, after in vitro EPO exposure and transplantation, in five different hematopoietic cell lineages, and observed the occurrence of high-output Myeloid-Erythroid-megaKaryocyte (MEK)-biased and Myeloid-B-cell-Dendritic cell (MBDC)-biased clones. ScRNAseq analysis of in vitro EPO-exposed HSCs revealed upregulation of erythroid associated genes in a subset of HSCs. Collectively, as well as demonstrating a direct effect of EPO on HSCs, our results suggest an EPO-mediated induction of MEK-bias in multi-outcome HSCs, and that this change in output is functionally compensated by MBDC-biased HSCs.

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“…CD56 bright NK cells are thought to give rise to CD56 dim NK cells based upon in vitro, in vivo, transplantation, and humanized mouse models . Despite these findings, which include longer telomeres in CD56 bright NK cells and the early appearance of CD56 bright NK cells following transplantation, the mechanism by which this transition is regulated is not defined, and the precise physiological relationship between the two subsets is called into question by recent studies in non‐human primates that suggests the two subsets have independent origins …”

Section: Human Nk Cell Development Differentiation and Functionmentioning

confidence: 99%

“…[24][25][26][27][28][29] Despite these findings, which include longer telomeres in CD56 bright NK cells 27 and the early appearance of CD56 bright NK cells following transplantation, 28,29 the mechanism by which this transition is regulated is not defined, and the precise physiological relationship between the two subsets is called into question by recent studies in non-human primates that suggests the two subsets have independent origins. 30,31 The difficulty in understanding human NK cell development has arisen from several factors. NK cell development and terminal maturation is a process with much greater plasticity than T or B cell development, including much less rigorous tissue restriction.…”

Section: H Uman Nk Cell De Velopment D Ifferentiati On and Fun Cmentioning

confidence: 99%

Emerging insights into human health and NK cell biology from the study of NK cell deficiencies

Mace

Orange

2018

Immunological Reviews

127

101

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Human NK cells are innate immune effectors that play a critical roles in the control of viral infection and malignancy. The importance of their homeostasis and function can be demonstrated by the study of patients with primary immunodeficiencies (PID), which are part of the family of diseases known as inborn defects of immunity. While NK cells are affected in many PIDs in ways that may contribute to a patient’s clinical phenotype, a small number of PIDs have an NK cell abnormality as their major immunological defect. These PIDs can be collectively referred to as NK cell deficiency disorders (NKD), and include effects upon NK cell numbers, subsets and/or functions. The clinical impact of NKD can be severe including fatal viral infection, with particular susceptibility to herpesviral infections, such as cytomegalovirus, varicella zoster virus and Epstein-Barr virus. While NKD is rare, studies of these diseases are important for defining specific requirements for human NK cell development and homeostasis. New themes in NK cell biology are emerging through the study of both known and novel NKD, particularly those affecting cell cycle and DNA damage repair, as well as broader PIDs having substantive impact upon NK cells. In addition, the discovery of NKD that affect other innate lymphoid cell (ILC) subsets opens new doors for better understanding the relationship between conventional NK cells and other ILC subsets. Here we describe the biology underlying human NKD, particularly in the context of new insights into innate immune cell function, including a discussion of recently described NKD with accompanying effects on ILC subsets. Given the impact of these disorders upon human immunity with a common focus upon NK cells, the unifying message of a critical role for NK cells in human host defense singularly emerges.

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Geographic clonal tracking in macaques provides insights into HSPC migration and differentiation

Abstract: Wu et al. use barcode tracking to uncover prolonged geographic bone marrow segregation of regenerating hematopoietic stem and progenitor cell clones after transplantation and provide evidence for local bone marrow production of T cells.

Cited by 35 publications

References 56 publications

Aberrant Clonal Hematopoiesis Following Lentiviral Transduction of HSPC in a Rhesus Macaque

Aberrant Clonal Hematopoiesis Following Lentiviral Transduction of HSPC in a Rhesus Macaque

Erythropoietin directly remodels the clonal composition of murine hematopoietic multipotent progenitor cells

Emerging insights into human health and NK cell biology from the study of NK cell deficiencies

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