Human mature erythroblasts are resistant to apoptosis

Hristoskova, Sashka; Holzgreve, Wolfgang; Hahn, Sinuhe; Rusterholz, Corinne

doi:10.1016/j.yexcr.2006.12.018

Cited by 10 publications

(13 citation statements)

References 30 publications

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“…1C). Trypan blue exclusion indicated that 98% of the cells were viable at day 8 (data not shown), consistent with the finding that maturing erythroid cells are resistant to apoptosis (9,36).…”

Section: Human K562 Cells Induced For Erythroid Maturation Showsupporting

confidence: 86%

mRNA Silencing in Human Erythroid Cell Maturation

Naarmann

Harnisch

Flach

et al. 2008

Journal of Biological Chemistry

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Erythroid precursor cells undergo nuclear extrusion and degradation of mitochondria when they mature to erythrocytes. It has been suggested before that the reticulocyte 15-lipoxygenase (r15-LOX) plays an important role in initiating the breakdown of mitochondria in rabbit reticulocytes. The expression of rabbit r15-LOX is regulated by the heterogeneous nuclear ribonucleoproteins (hnRNP) K and E1 at the translational level. However, this mechanism has never been confirmed in human erythropoiesis. Based on K562 cells we have set up an inducible human erythroid cell system. We show that, during induction, K562 cells exhibit changes in morphology and protein expression that are characteristic for terminal erythroid maturation: nuclear exclusion, expression of endogenous human r15-LOX regulated by hnRNP K and hnRNP E1, and loss of mitochondria. Importantly, induction of terminal erythroid maturation in primary human CD34؉ cells recapitulated the results obtained in K562 cells. Employing the physiologically relevant K562 cell system we uncovered a new mechanism of interdependent posttranscriptional regulation of gene expression. The timely expression of the tyrosine kinase c-Src, which phosphorylates hnRNP K in later stages, is controlled by hnRNP K in early stages of erythroid maturation. hnRNP K binds to the 3-untranslated region of the c-Src mRNA and inhibits its translation by blocking 80 S ribosome formation. In premature erythroid cells, small interfering RNA-mediated knockdown of hnRNP K, but not of hnRNP E1, leads to the de-repression of c-Src synthesis.

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Section: Human K562 Cells Induced For Erythroid Maturation Showsupporting

confidence: 86%

mRNA Silencing in Human Erythroid Cell Maturation

Naarmann

Harnisch

Flach

et al. 2008

Journal of Biological Chemistry

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“…After day 10, cell expansion remained marginal (1.8 AE 0.4 fold increase from days 10 to 14, N ¼ 3), while differentiation proceeded. At the end of the culture period, mature orthochromatophilic erythroblasts and erythrocytes comprised approximately 90% of the total cultured cells (Hristoskova et al, 2007). In addition, cells that appeared to be monocytes by morphological criterion accounted for 3-5% of the cultures (data not shown).…”

Section: Resultsmentioning

confidence: 91%

“…These cultures permit reasonably synchronous differentiation of erythroid progenitors through the sequential stages of erythroblast maturation (from immature pro-, basophilic-, polychromatophilic-, to mature orthochromatic-erythroblasts) (Zermati et al, 2000). At day 7, the cultures consisted of >95% of immature erythroblasts (pro-and basophilic erythroblasts) as assessed by morphological inspection (data not shown) (Hristoskova et al, 2007). By day 10, the cell population had expanded 7.0 AE 1.6 fold (N ¼ 3) and contained predominantly polychromatophilic erythroblasts.…”

Section: Resultsmentioning

confidence: 92%

“…com. ] activation of several caspases, among which the initiator caspase-9 and the effector caspase-3 (Zermati et al, 2001;Hristoskova et al, 2007), AIF and CAD activation could possibly occur in these cells. However, our study shows that neither ICAD, in agreement with previous findings (Zermati et al, 2001), nor AIF are likely involved in erythroblast-specific chromatin digestion.…”

Section: Discussionmentioning

confidence: 99%

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The chromatin of differentiating erythroblasts is cleaved into large size fragments independent of caspase activated DNase and apoptosis inducing factor

Hristoskova

Holzgreve

Hahn

et al. 2007

Journal Cellular Physiology

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Erythroblast cell differentiation involves self-controlled and limited nuclear proteolysis prior nucleus loss. Early evidence suggests that apoptotic-like pathways are activated during this process. The chromatin of developing erythroblasts becomes fragmented in vivo, however, the exact mechanisms and molecules involved remain elusive. In this study, erythroblasts were differentiated in culture from CD34-enriched umbilical cord blood progenitor cells and the characteristics of DNA fragmentation were examined. This analysis shows that the chromatin of differentiating erythroblasts is cleaved into discrete fragments of 50-200 kb. This process most likely involves one or several endonucleases as we detect in vivo double strand DNA cleavage. However, major players of the apoptotic DNA degradation, caspase activated DNase and apoptosis inducing factor, are not activated in these cells. Therefore, our data suggests that erythroblast chromatin degradation may involve enzymes distinct form those active in apoptotic cells.

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“…To date, none have achieved yield and stringency o� �etal cell isolation acceptable �or clinical applications, including e�ficiency, e��ectiveness and cost [8,63]. An additional drawback is the o�ten poor quality o� the genetic material in �etal cells, which, at least in �etal erythroblasts, is related to the process o� enucleation that erythrocytes undergo as they mature [64,65]. With respect to the diagnosis o� monogenic disorders based on PCR analysis, this presents a major limitation, and probably explains the high rates o� ADO that have been observed when analyzing isolated �etal NRBCs [66,67].…”

Section: Review Traeger-synodinos Vrettou and Kanavakismentioning

confidence: 99%

Prenatal, noninvasive and preimplantation genetic diagnosis of inherited disorders: hemoglobinopathies

Traeger-Synodinos

Vrettou

Kanavakis

2011

Expert Review of Molecular Diagnostics

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Disorders of hemoglobin synthesis have been used as a prototype for the development of most approaches for prenatal diagnosis (PND). PND for hemoglobinopathies based on molecular analysis of trophoblast or amniocyte DNA has accumulated approximately 30 years of experience. Disadvantages with conventional PND include 'invasive' fetal sampling and the need to terminate affected ongoing pregnancies. New developments are directed towards improving both the timing and/or safety of procedures. Preimplantation genetic diagnosis, an established procedure with 20 years of clinical application, avoids the need to terminate affected pregnancies through the identification and selective transfer of unaffected in vitro fertilization embryos. Approaches towards 'noninvasive' PND, through analyzing fetal cells or free fetal DNA present in the circulation of pregnant women, are a focus of ongoing research. Overall, PND, preimplantation genetic diagnosis (and potentially 'noninvasive' PND) represent valuable reproductive options for couples at risk of having a child affected with a severe inherited disease.

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Human mature erythroblasts are resistant to apoptosis

Cited by 10 publications

References 30 publications

mRNA Silencing in Human Erythroid Cell Maturation

mRNA Silencing in Human Erythroid Cell Maturation

The chromatin of differentiating erythroblasts is cleaved into large size fragments independent of caspase activated DNase and apoptosis inducing factor

Prenatal, noninvasive and preimplantation genetic diagnosis of inherited disorders: hemoglobinopathies

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