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All blood and immune cells are produced from the multipotent hematopoietic stem cells (HSCs) by the process of hematopoiesis. However, they all have a limited life span. In addition, many are depleted in immune surveillance or combatting an injury or infection. This makes blood one of the most regenerative tissues. Hematopoiesis helps replenish these blood and immune cells, restoring the body's normal functioning. However, overproduction of blood and immune cells can make them cancerous or...
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The process of blood cell formation is called hematopoiesis. Hematopoiesis starts early during development, on the seventh day of embryogenesis. This phase of hematopoiesis is called the primitive wave, wherein the extraembryonic yolk sac allows the production of erythroid cells and endothelial cells from a common precursor called hemangioblast. The erythroid cells provide oxygen to support the growth of the rapidly dividing embryo. Hemangioblasts later develop into hematopoietic stem cells or...
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Cell polarity is the asymmetric distribution of cellular and membrane components, making one side of the cell different from the other. This polarity is essential to many processes such as embryogenesis, axon migration, glucose transport across epithelial cells, and directional cell migration. A migrating cell responds to intracellular or extracellular signals via molecular cascades that reorganize the actin cytoskeleton to establish this polarity. In these cells, the Rho family proteins Cdc42,...
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Cdc42-Borg4-Septin7 axis regulates HSC polarity and function.

Ravinder Kandi1, Katharina Senger1, Ani Grigoryan1

  • 1Institute of Molecular Medicine, Ulm University, Ulm, Germany.

EMBO Reports
|October 18, 2021
PubMed
Summary

Aging hematopoietic stem cells (HSCs) show altered protein distribution due to Cdc42 activity. A newly identified Cdc42-Borg4-Septin7 pathway is crucial for HSC polarity and function.

Keywords:
Borg4Cdc42HSCsSeptin7polarity

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Area of Science:

  • Cell Biology
  • Hematopoiesis
  • Stem Cell Aging

Background:

  • Aging hematopoietic stem cells (HSCs) exhibit elevated Cdc42 activity and disrupted protein distribution.
  • The precise mechanisms by which Cdc42 regulates HSC polarity remain unclear.
  • Binder of RhoGTPases (Borg) proteins are known Cdc42 effectors that influence the cytoskeleton.

Purpose of the Study:

  • To elucidate the role of Cdc42 effector proteins in maintaining HSC polarity.
  • To investigate the interaction between Cdc42, Borg proteins, and the Septin network in HSCs.
  • To determine the functional consequences of disrupting this axis on HSC engraftment and progenitor frequency.

Main Methods:

  • Co-immunoprecipitation assays to identify protein interactions.
  • Genetic deletion models (Borg4 or Septin7 knockout) in mice.
  • Flow cytometry to assess HSC polarity and progenitor populations (LMPPs).
  • Bone marrow transplantation assays to evaluate HSC engraftment potential.

Main Results:

  • Cdc42 directly interacts with Borg4, which subsequently interacts with Septin7.
  • This Cdc42-Borg4-Septin7 axis regulates the polar distribution of these proteins within HSCs.
  • Genetic deletion of Borg4 or Septin7 impairs HSC polarity and reduces their engraftment capacity.
  • Loss of Borg4 or Septin7 also leads to a decreased frequency of lymphoid-primed multipotent progenitors (LMPPs).

Conclusions:

  • A novel Cdc42-Borg4-Septin7 signaling axis is essential for maintaining polarity and function in hematopoietic stem cells.
  • This pathway is critical for HSC engraftment potential and the maintenance of progenitor populations.
  • The findings highlight Borgs and Septins as key regulators of stem cell compartmentalization and aging.