Modelling human haemoglobin switching

Diepstraten, Sarah T; Hart, Adam H.

doi:10.1016/j.blre.2018.06.001

Cited by 9 publications

(7 citation statements)

References 163 publications

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“…When substituting in vivo models with in vitro cell systems, one must have confidence that the latter faithfully recapitulates the former. 3,33,34 We therefore compared the phenotypes of specific genetic manipulations in EB-derived cells with their counterparts in primary cells. We used the α-globin gene cluster as a well characterized model of mammalian gene expression.…”

Section: Resultsmentioning

confidence: 99%

ScalableIn VitroProduction of Defined Mouse Erythroblasts

Francis¹,

Harold²,

Beagrie³

et al. 2020

Preprint

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Mouse embryonic stem cells (mESCs) can be manipulated in vitro to recapitulate the process of erythropoiesis, during which multipotent cells undergo lineage specification, differentiation and maturation to produce erythroid cells. Although useful for identifying specific progenitors and precursors, this system has not been fully exploited as a source of cells to analyse erythropoiesis. Here, we establish a protocol in which characterised erythroblasts can be isolated in a scalable manner from differentiated embryoid bodies (EBs). Using transcriptional and epigenetic analysis, we demonstrate that this system faithfully recapitulates normal primitive erythropoiesis and fully reproduces the effects of natural and engineered mutations seen in primary cells obtained from mouse models. We anticipate this system to be of great value in reducing the time and costs of generating and maintaining mouse lines in a number of research scenarios.Key PointsScalable purification of primitive-like erythroid cells from in vitro differentiated mESCs offers tractable tools for genetic studiesIn vitro derived erythroid cells recapitulate wild type and engineered mutation phenotypes observed in primary cells obtained from mouse models

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Section: Resultsmentioning

confidence: 99%

ScalableIn VitroProduction of Defined Mouse Erythroblasts

Francis¹,

Harold²,

Beagrie³

et al. 2020

Preprint

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“…This expression leads to the production of fetal hemoglobin, HbF. In adults the gamma globin gene is repressed, but most humans express low levels of HbF, approximately 1-5% in circulating erythrocytes (for recent reviews, see [56,57]). This percentage increases in patients with inherited bone marrow failure syndromes and during recovery from bone marrow transplant [58][59][60].…”

Section: Stress Erythropoiesis Maintains Erythroid Homeostasis When Smentioning

confidence: 99%

Stress Erythropoiesis is a Key Inflammatory Response

Paulson

Ruan

et al. 2020

Cells

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Bone marrow medullary erythropoiesis is primarily homeostatic. It produces new erythrocytes at a constant rate, which is balanced by the turnover of senescent erythrocytes by macrophages in the spleen. Despite the enormous capacity of the bone marrow to produce erythrocytes, there are times when it is unable to keep pace with erythroid demand. At these times stress erythropoiesis predominates. Stress erythropoiesis generates a large bolus of new erythrocytes to maintain homeostasis until steady state erythropoiesis can resume. In this review, we outline the mechanistic differences between stress erythropoiesis and steady state erythropoiesis and show that their responses to inflammation are complementary. We propose a new hypothesis that stress erythropoiesis is induced by inflammation and plays a key role in maintaining erythroid homeostasis during inflammatory responses.

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“…Up to 6 weeks post-birth, fetal hemoglobin (HbF) is formed by two alpha and two gamma globin chains, coded by gene loci on chromosomes 16 and 11, respectively (Sankaran and Nathan, 2010). At 6-weeks post-partum, erythrocyte progenitors begin to produce adult (HbA) hemoglobin (Sankaran and Nathan, 2010;Diepstraten and Hart, 2019). Unlike HbF, HbA is made of two alpha and two beta globin chains and typically forms 90-95% of the total hemoglobin in adult erythrocytes, although this is subject to variation (Wood et al, 1975;Kato et al, 2018).…”

Section: Hemoglobin Developmentmentioning

confidence: 99%

“…The resulting increased recruitment of erythroid progenitor cells (which can produce red blood cells) is associated with an overall higher HbF synthesis (Wood et al, 1976;Agrawal et al, 2014). Higher levels of HbF increase SCD lifespan, reduce the incidence of acute chest syndrome and occurrence of VOCs, stroke and chronic organ damage (Ballas et al, 1989;Strouse and Heeney, 2012;Diepstraten and Hart, 2019;Lagunju et al, 2019).…”

Section: Disease-modifying Drugs Hydroxyureamentioning

confidence: 99%

In utero Therapy for the Treatment of Sickle Cell Disease: Taking Advantage of the Fetal Immune System

Cortabarria

Makhoul

Strouboulis

et al. 2021

Front. Cell Dev. Biol.

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Sickle Cell Disease (SCD) is an autosomal recessive disorder resulting from a β-globin gene missense mutation and is among the most prevalent severe monogenic disorders worldwide. Haematopoietic stem cell transplantation remains the only curative option for the disease, as most management options focus solely on symptom control. Progress in prenatal diagnosis and fetal therapeutic intervention raises the possibility of in utero treatment. SCD can be diagnosed prenatally in high-risk patients using chorionic villus sampling. Among the possible prenatal treatments, in utero stem cell transplantation (IUSCT) shows the most promise. IUSCT is a non-myeloablative, non-immunosuppressive alternative conferring various unique advantages and may also offer safer postnatal management. Fetal immunologic immaturity could allow engraftment of allogeneic cells before fetal immune system maturation, donor-specific tolerance and lifelong chimerism. In this review, we will discuss SCD, screening and current treatments. We will present the therapeutic rationale for IUSCT, examine the early experimental work and initial human experience, as well as consider primary barriers of clinically implementing IUSCT and the promising approaches to address them.

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Modelling human haemoglobin switching

Cited by 9 publications

References 163 publications

ScalableIn VitroProduction of Defined Mouse Erythroblasts

ScalableIn VitroProduction of Defined Mouse Erythroblasts

Stress Erythropoiesis is a Key Inflammatory Response

In utero Therapy for the Treatment of Sickle Cell Disease: Taking Advantage of the Fetal Immune System

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