Elucidating regulators of red blood cell development in health and disease

Taha Sen

Research output: ThesisDoctoral Thesis (compilation)

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Red blood cells are are plentiful, flexible and essential. They are the most abundant cell in our body and their main
object is to carry oxygen, which is essential for cellular respiration. The formation of red blood cells is called
erythropoiesis. Erythropoiesis is intimately coupled to cell division and mitochondrial function. Aberrations in these
two processes are often associated with red blood cell disorders, which result in anemia. Anemia is characterized
by the lack of red blood cells and/or reduced hemoglobin concentrations resulting in reduced oxygen transport to
the tissue and inevitable to reduced quality of life and increased mortality. My aim in this thesis has been to
deepen our understanding of how erythropoiesis is regulated in health and disease
In the first paper we demonstrated that anemia caused by pRb deficiency was due to disrupted differentiation with
underlying impairment to mitochondrial function at the orthochromatic erythroblast stage. The MDS-like phenotype
of pRb deficient mice could be rescued by enhanced PPAR pathway signaling, an important signaling axis in
mitochondrial biogenesis, in vivo either genetically or therapeutically.
In the second paper we translated our findings in the mouse to a human setting by inhibiting PPAR signaling. We
demonstrated that perturbed PPAR signaling 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. We showed that PPAR signaling is important for iron, heme and globin homeostasis.
Furthermore we demonstrated that PPAR signaling affects cell cycle exit indicating that there is a mutual
regulation between cell cycle progression and mitochondrial function during terminal erythropoiesis.
In the third paper we demonstrated that Ypel4, which is highly expressed in orthochromatic erythroblasts, is
important for the integrity of red blood cell membrane. Ypel4 null erythroblast had reduced deformability and were
cleared at an increased rate. The phenotype resembled defects normally observed in human hereditary
membrane disorders.
Overall the papers included in this thesis highlight mechanisms and genes important for terminal erythropoiesis
specifically in the orthochromatic erythroblast. We further described disease associated with the different
perturbations to erythropoiesis. The work presented
Original languageEnglish
Awarding Institution
  • Department of Laboratory Medicine
  • Flygare, Johan, Supervisor
  • Singbrant, Sofie, Assistant supervisor
  • Richter, Johan, Assistant supervisor
Award date2021 Nov 17
Place of PublicationLund
ISBN (Print)978-91-8021-128-4
Publication statusPublished - 2021

Bibliographical note

Defence details
Date: 2021-11-17
Time: 13:00
Place: BMC I1345, Sölvegatan 17 i Lund. Join by Zoom: https://lu-se.zoom.us/j/63884757012
External reviewer(s)
Name: Palis, James
Title: Professor
Affiliation: University of Rochester Medical Center, Rochester, NY, USA

Subject classification (UKÄ)

  • Hematology


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