“…3 C). In conclusion, reduced expression of PGC1β results in perturbed formation of early erythroid progenitors and impaired terminal erythroid differentiation with an accumulation of polychromatic erythroblasts and a subsequent reduction of more mature erythroblasts, a phenotype that is reminiscent of the refractory anemia seen in many MDS patients 27 and the MDS-like anemia we have previously reported on in mouse 21 . Figure 3 Decreased expression of PGC1β in CB derived CD34 + cells results in perturbed formation of early erythroid progenitors and impaired enucleation.…”
Section: Introductionmentioning
confidence: 70%
“…The only study to date directly evaluating the role of PGC-1 coactivators during RBC development demonstrates that compound deletion of the related Pgc1 α and Pgc1 β during embryonic development in mouse results in anemia due to deregulation of globin genes 26 . Furthermore, we recently demonstrated that perturbed PGC1β expression in response to pRb-deletion in mice results in a developmental block during terminal erythropoiesis and anemia reminiscent of that reported in Myelodysplastic syndrome (MDS) 21 , 27 . Importantly, the MDS-like anemia could be rescued by enhanced PPAR-signaling, either through PGC1β over-expression or Bezafibrate treatment 21 , indicating that PGC1β plays a functional role in the anemic phenotype.…”
Section: Introductionmentioning
confidence: 89%
“…Furthermore, we recently demonstrated that perturbed PGC1β expression in response to pRb-deletion in mice results in a developmental block during terminal erythropoiesis and anemia reminiscent of that reported in Myelodysplastic syndrome (MDS) 21 , 27 . Importantly, the MDS-like anemia could be rescued by enhanced PPAR-signaling, either through PGC1β over-expression or Bezafibrate treatment 21 , indicating that PGC1β plays a functional role in the anemic phenotype. Notably, PGC1β is haplo-insufficient in the chromosome 5q deletion subtype of MDS (del(5q) MDS) 28 and deregulation of core mitochondrial pathways and acquired mtDNA mutations have been reported in MDS-patients with anemia 29 , generally in genes related to iron and heme homeostasis 12 , 30 , 31 .…”
Section: Introductionmentioning
confidence: 89%
“…Pgc-1β display increased expression during terminal erythroid differentiation 21 . However, its function has mainly been studied in adipocytes, hepatic-, cardiac and skeletal tissues 19 , 22 – 25 , while the role of PGC-1β in erythropoiesis remains largely unknown.…”
Production of red blood cells relies on proper mitochondrial function, both for their increased energy demands during differentiation and for proper heme and iron homeostasis. Mutations in genes regulating mitochondrial function have been reported in patients with anemia, yet their pathophysiological role often remains unclear. PGC1β is a critical coactivator of mitochondrial biogenesis, with increased expression during terminal erythroid differentiation. The role of PGC1β has however mainly been studied in skeletal muscle, adipose and hepatic tissues, and its function in erythropoiesis remains largely unknown. Here we show that perturbed PGC1β expression in human hematopoietic stem/progenitor cells from both bone marrow and cord blood results in impaired formation of early erythroid progenitors and delayed terminal erythroid differentiation in vitro, with accumulations of polychromatic erythroblasts, similar to MDS-related refractory anemia. Reduced levels of PGC1β resulted in deregulated expression of iron, heme and globin related genes in polychromatic erythroblasts, and reduced hemoglobin content in the more mature bone marrow derived reticulocytes. Furthermore, PGC1β knock-down resulted in disturbed cell cycle exit with accumulation of erythroblasts in S-phase and enhanced expression of G1-S regulating genes, with smaller reticulocytes as a result. Taken together, we demonstrate that PGC1β is directly involved in production of hemoglobin and regulation of G1-S transition and is ultimately required for proper terminal erythroid differentiation.
“…3 C). In conclusion, reduced expression of PGC1β results in perturbed formation of early erythroid progenitors and impaired terminal erythroid differentiation with an accumulation of polychromatic erythroblasts and a subsequent reduction of more mature erythroblasts, a phenotype that is reminiscent of the refractory anemia seen in many MDS patients 27 and the MDS-like anemia we have previously reported on in mouse 21 . Figure 3 Decreased expression of PGC1β in CB derived CD34 + cells results in perturbed formation of early erythroid progenitors and impaired enucleation.…”
Section: Introductionmentioning
confidence: 70%
“…The only study to date directly evaluating the role of PGC-1 coactivators during RBC development demonstrates that compound deletion of the related Pgc1 α and Pgc1 β during embryonic development in mouse results in anemia due to deregulation of globin genes 26 . Furthermore, we recently demonstrated that perturbed PGC1β expression in response to pRb-deletion in mice results in a developmental block during terminal erythropoiesis and anemia reminiscent of that reported in Myelodysplastic syndrome (MDS) 21 , 27 . Importantly, the MDS-like anemia could be rescued by enhanced PPAR-signaling, either through PGC1β over-expression or Bezafibrate treatment 21 , indicating that PGC1β plays a functional role in the anemic phenotype.…”
Section: Introductionmentioning
confidence: 89%
“…Furthermore, we recently demonstrated that perturbed PGC1β expression in response to pRb-deletion in mice results in a developmental block during terminal erythropoiesis and anemia reminiscent of that reported in Myelodysplastic syndrome (MDS) 21 , 27 . Importantly, the MDS-like anemia could be rescued by enhanced PPAR-signaling, either through PGC1β over-expression or Bezafibrate treatment 21 , indicating that PGC1β plays a functional role in the anemic phenotype. Notably, PGC1β is haplo-insufficient in the chromosome 5q deletion subtype of MDS (del(5q) MDS) 28 and deregulation of core mitochondrial pathways and acquired mtDNA mutations have been reported in MDS-patients with anemia 29 , generally in genes related to iron and heme homeostasis 12 , 30 , 31 .…”
Section: Introductionmentioning
confidence: 89%
“…Pgc-1β display increased expression during terminal erythroid differentiation 21 . However, its function has mainly been studied in adipocytes, hepatic-, cardiac and skeletal tissues 19 , 22 – 25 , while the role of PGC-1β in erythropoiesis remains largely unknown.…”
Production of red blood cells relies on proper mitochondrial function, both for their increased energy demands during differentiation and for proper heme and iron homeostasis. Mutations in genes regulating mitochondrial function have been reported in patients with anemia, yet their pathophysiological role often remains unclear. PGC1β is a critical coactivator of mitochondrial biogenesis, with increased expression during terminal erythroid differentiation. The role of PGC1β has however mainly been studied in skeletal muscle, adipose and hepatic tissues, and its function in erythropoiesis remains largely unknown. Here we show that perturbed PGC1β expression in human hematopoietic stem/progenitor cells from both bone marrow and cord blood results in impaired formation of early erythroid progenitors and delayed terminal erythroid differentiation in vitro, with accumulations of polychromatic erythroblasts, similar to MDS-related refractory anemia. Reduced levels of PGC1β resulted in deregulated expression of iron, heme and globin related genes in polychromatic erythroblasts, and reduced hemoglobin content in the more mature bone marrow derived reticulocytes. Furthermore, PGC1β knock-down resulted in disturbed cell cycle exit with accumulation of erythroblasts in S-phase and enhanced expression of G1-S regulating genes, with smaller reticulocytes as a result. Taken together, we demonstrate that PGC1β is directly involved in production of hemoglobin and regulation of G1-S transition and is ultimately required for proper terminal erythroid differentiation.
“…S4A, C, E, and G.). For example, the deletion of Rb caused moderate anemia, induced inhibition of mitochondrial biogenesis, decreased OXPHOS pathway activity, and disturbed heme production and iron transport [46,47]. Thus, these results suggest that the blood transcriptome could explain and mirror the detailed hemopoietic mechanism induced by rAdV-hEPO injection.…”
The World Anti-Doping Agency (WADA) has prohibited gene doping in the context of progress in gene therapy. In addition, there is a risk of the EPO gene being applied in gene doping among athletes. Along with this, development of a gene-doping test has been underway in worldwide. Here, we had two purposes: to develop a robust gene doping mouse model using the human EPO gene (hEPO) transferred using recombinant adenovirus (rAdV) as a vector and to develop a detection method to prove gene doping using this model. The rAdV including the hEPO gene were injected intravenously to transfer the gene to the liver. After injection, the mice developed significantly increased red blood cell counts in whole blood and increased gene expressions of hematopoietic markers in the spleen, indicating successful development of the gene doping model. Next, we detected direct and indirect proof of gene doping in whole blood DNA and RNA using qPCR assay and RNA sequencing. Proof was detected in one drop of whole blood DNA and RNA over a long period; furthermore, the overall RNA expression profiles significantly changed. Therefore, we have advanced detection of hEPO gene doping in humans.
The Feline Leukemia Virus Subgroup C Receptor 1a (FLVCR1a) is a member of the SLC49 Major Facilitator Superfamily of transporters. Initially recognized as the receptor for the retrovirus responsible of pure red cell aplasia in cats, nearly two decades since its discovery, FLVCR1a remains a puzzling transporter, with ongoing discussions regarding what it transports and how its expression is regulated. Nonetheless, despite this, the substantial body of evidence accumulated over the years has provided insights into several critical processes in which this transporter plays a complex role, and the health implications stemming from its malfunction. The present review intends to offer a comprehensive overview and a critical analysis of the existing literature on FLVCR1a, with the goal of emphasising the vital importance of this transporter for the organism and elucidating the interconnections among the various functions attributed to this transporter.
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