Neonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transition

Elagib, Kamaleldin E.; Lu, Chih Huan; Mosoyan, Goar; Khalil, Shadi; Zasadzińska, Ewelina; Foltz, Daniel R.; Balogh, Péter; Gru, Alejandro A.; Fuchs, Deborah; Rimsza, Lisa M.; Verhoeyen, Els; Sansó, Miriam; Fisher, Robert P; Iancu‐Rubin, Camelia; Goldfarb, Adam N.

doi:10.1172/jci88936

Cited by 41 publications

(70 citation statements)

References 58 publications

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“…human ontogenic master switch, restricts megakaryocyte development by modulating a lineage-specific P-TEFb activation mechanism, revealing potential strategies toward enhancing platelet production (Elagib et al, 2017). In this study, the expression of IGF2BP3 in RSS chickens was examined by qRT-PCR.…”

Section: Discussionmentioning

confidence: 99%

Runting and Stunting Syndrome Is Associated With Mitochondrial Dysfunction in Sex-Linked Dwarf Chicken

Luo

et al. 2020

Front. Genet.

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Runting and stunting syndrome (RSS) in chicken are commonly known as "frozen chicken." The disease is characterized by lower body weight and slow growth and the incidence rate is widely 5%-20% in sex-linked dwarf (SLD) chickens. However, the etiology of RSS in chickens has plagued researchers for several decades. In this study, histopathology studies demonstrated that the hepatocytes of the RSS chickens contain many mitochondria with damaged and outer and inner membrane along with vacuolar hydropic degeneration. No mtDNA mutation was detected, but our microarray data showed that RSS chickens exhibited abnormal expression of genes, many of which are involved in oxidative phosphorylation (OXPHOS) and fatty acid metabolism. In particular, nuclear gene IGF2BP3 was upregulated in RSS chickens' liver cells. The abnormal expression of these genes is likely to impair the OXPHOS, resulting in reduced ATP synthesis in the hepatocytes of the RSS chickens, which may in turn leads to poor weight gain and retarded growth or stunting of chicks. Our findings suggest that mitochondria dysfunction rather than chronic inflammation is responsible for the reduced growth and RSS in SLD chickens. Mutations in GHR have been shown to compromise mitochondrial function in SLD chickens. Since the mitochondrial damage in the RSS chicken is more severe, we suggest that extra genes are likely to be affected to exacerbate the phenotype.

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Section: Discussionmentioning

confidence: 99%

Runting and Stunting Syndrome Is Associated With Mitochondrial Dysfunction in Sex-Linked Dwarf Chicken

Luo

et al. 2020

Front. Genet.

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“…Following knockdown of IGF2BP3 expression, fetal megakaryocytes are transformed to a growth-arrested, adult-like state (Elagib et al, 2017). No direct role in erythropoiesis has been attributed to the NETO2 and BCAT1 genes also up-regulated in FL-derived erythroblast cells.…”

Section: Discussionmentioning

confidence: 99%

Comparison of gene expression profiles between human erythroid cells derived from fetal liver and adult peripheral blood

Tangprasittipap

Kaewprommal

Sripichai

et al. 2018

PeerJ

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BackgroundA key event in human development is the establishment of erythropoietic progenitors in the bone marrow, which is accompanied by a fetal-to-adult switch in hemoglobin expression. Understanding of this event could lead to medical application, notably treatment of sickle cell disease and β-thalassemia. The changes in gene expression of erythropoietic progenitor cells as they migrate from the fetal liver and colonize the bone marrow are still rather poorly understood, as primary fetal liver (FL) tissues are difficult to obtain.MethodsWe obtained human FL tissue and adult peripheral blood (AB) samples from Thai subjects. Primary CD34+ cells were cultured in vitro in a fetal bovine serum-based culture medium. After 8 days of culture, erythroid cell populations were isolated by flow cytometry. Gene expression in the FL- and AB-derived cells was studied by Affymetrix microarray and reverse-transcription quantitative PCR. The microarray data were combined with that from a previous study of human FL and AB erythroid development, and meta-analysis was performed on the combined dataset.ResultsFL erythroid cells showed enhanced proliferation and elevated fetal hemoglobin relative to AB cells. A total of 1,391 fetal up-regulated and 329 adult up-regulated genes were identified from microarray data generated in this study. Five hundred ninety-nine fetal up-regulated and 284 adult up-regulated genes with reproducible patterns between this and a previous study were identified by meta-analysis of the combined dataset, which constitute a core set of genes differentially expressed between FL and AB erythroid cells. In addition to these core genes, 826 and 48 novel genes were identified only from data generated in this study to be FL up- and AB up-regulated, respectively. The in vivo relevance for some of these novel genes was demonstrated by pathway analysis, which showed novel genes functioning in pathways known to be important in proliferation and erythropoiesis, including the mitogen-activated protein kinase (MAPK) and the phosphatidyl inositol 3 kinase (PI3K)-Akt pathways.DiscussionThe genes with upregulated expression in FL cells, which include many novel genes identified from data generated in this study, suggest that cellular proliferation pathways are more active in the fetal stage. Erythroid progenitor cells may thus undergo a reprogramming during ontogenesis in which proliferation is modulated by changes in expression of key regulators, primarily MYC, and others including insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), neuropilin and tolloid-like 2 (NETO2), branched chain amino acid transaminase 1 (BCAT1), tenascin XB (TNXB) and proto-oncogene, AP-1 transcription factor subunit (JUND). This reprogramming may thus be necessary for acquisition of the adult identity and switching of hemoglobin expression.

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“…For example, suppression of IGF2BP3 via small molecules or gene editing could allow for further maturation of megakaryocytes, or selective inhibition of the metalloproteinase ADAM17 could improve platelet functionality by preventing glycoprotein Ibα/CD42b shedding in vitro. 30,64 …”

Section: Methods To Increase Ipsc-derived Progenitor and Megakaryocytmentioning

confidence: 99%

“…25 Recent evidence suggests IGF2BP3 as a master switch driving immature fetal/neonatal to adult megakaryopoiesis. 30 Overall, a better understanding of the regulatory and functional changes that occur during megakaryocyte ontogeny are critical for generating high quality megakaryocytes and platelets for transfusion purposes.…”

Section: Megakaryocyte Ontogenymentioning

confidence: 99%

“…Other laboratories are trying to further mature in vitro-derived megakaryocytes to increase ploidy and ultimately increase platelet release by genetically manipulating maturation factors. 30 Despite current progress, much more work remains to be done before iPSC-derived megakaryocytes and platelets make their way into the clinic.…”

Section: Conclusion: Are We Ready For the Clinic?mentioning

confidence: 99%

See 1 more Smart Citation

Induced Pluripotent Stem Cell–Derived Megakaryocytes and Platelets for Disease Modeling and Future Clinical Applications

Borst

Sim

Poncz

et al. 2017

ATVB

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Platelets, derived from megakaryocytes, are anucleate cytoplasmic discs that circulate in the blood stream and play major roles in hemostasis, inflammation, and vascular biology. Platelet transfusions are utilized in a variety of medical settings to prevent life-threatening thrombocytopenia due to cancer therapy, other causes of acquired or inherited thrombocytopenia, and trauma. Currently, platelets used for transfusion purposes are donor-derived. However, there is a drive to generate non-donor sources of platelets to help supplement donor-derived platelets. Efforts have been made by many laboratories to generate in vitro platelets and optimize their production and quality. In vitro-derived platelets have the potential to be a safer, more uniform product, and genetic manipulation could allow for better treatment of patients that become refractory to donor-derived units. This review focuses on potential clinical applications of in vitro-derived megakaryocytes and platelets, current methods to generate and expand megakaryocytes from pluripotent stem cell sources, and the use of these cells for disease modeling.

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Neonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transition

Cited by 41 publications

References 58 publications

Runting and Stunting Syndrome Is Associated With Mitochondrial Dysfunction in Sex-Linked Dwarf Chicken

Runting and Stunting Syndrome Is Associated With Mitochondrial Dysfunction in Sex-Linked Dwarf Chicken

Comparison of gene expression profiles between human erythroid cells derived from fetal liver and adult peripheral blood

Induced Pluripotent Stem Cell–Derived Megakaryocytes and Platelets for Disease Modeling and Future Clinical Applications

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