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Regulation of Hematopoietic Stem Cells01:01

Regulation of Hematopoietic Stem Cells

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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 hematopoietic stem cells or HSCs are multipotent, meaning they can differentiate and give rise to all blood and immune cells. HSCs are maintained in the quiescent stage until an external stimulus initiates their differentiation. The multipotent HSCs exist as two heterogeneous populations, long-term repopulating cells (LTRC) and short-term repopulating cells (STRC). The two HSC populations have different surface markers or receptors and are classified based on quiescence and long-term...
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Role of Hematopoietic Growth Factors01:28

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Hematopoietic growth factors are molecules that regulate the differentiation rate of hematopoietic stem cells (HSCs). Erythropoietin (EPO), primarily produced by the kidneys, plays a crucial role in erythrocyte production. When oxygen levels in the blood are low, EPO is released into the bloodstream, reaching the bone marrow, where it stimulates HSCs to differentiate and mature into erythrocytes, which are vital for oxygen transport.
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MicroRNAs01:22

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MicroRNA (miRNA) are short, regulatory RNA transcribed from introns (non-coding regions of a gene) or intergenic regions (stretches of DNA present between genes). Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself, forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After the pre-miRNA...
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MicroRNA (miRNA) are short, regulatory RNA transcribed from introns—non-coding regions of a gene—or intergenic regions—stretches of DNA present between genes. Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After...
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Common myeloid progenitors (CMPs) are oligopotent cells that can differentiate into granulocytes and macrophages. Granulocytes and macrophages are essential for protecting the body against bacterial, viral, or fungal infections. They migrate from the bone marrow into the circulating blood to reach specific tissue sites where they differentiate and help in immune surveillance. However, they survive only for a few days and must be continuously made available to the organism to maintain a robust...
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The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function.

Christopher Mapperley1,2, Louie N van de Lagemaat1,2, Hannah Lawson2

  • 1Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.

The Journal of Experimental Medicine
|November 6, 2020
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The m6A reader YTHDF2 is crucial for maintaining hematopoietic stem cell function. Its absence leads to inflammation and impairs long-term blood cell production, underscoring m6A

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Area of Science:

  • Hematopoiesis research
  • RNA modification biology
  • Stem cell biology

Background:

  • N6-methyladenosine (m6A) mRNA modification regulates gene expression.
  • The m6A reader YTHDF2 promotes degradation of m6A-modified transcripts.
  • YTHDF2 deficiency impacts hematopoietic stem cell (HSC) function and leukemia.

Purpose of the Study:

  • To investigate the long-term effects of YTHDF2 deletion on HSC maintenance.
  • To understand the role of YTHDF2 in multilineage hematopoiesis.
  • To elucidate the relationship between YTHDF2, inflammation, and HSC function.

Main Methods:

  • Serial transplantation assays of Ythdf2-deficient HSCs.
  • Analysis of m6A-modified transcripts and inflammatory pathways.
  • Assessment of hematopoiesis in aged Ythdf2-deficient mice.

Main Results:

  • Ythdf2-deficient HSCs fail serial transplantation and show impaired multilineage potential.
  • Deletion of YTHDF2 leads to increased inflammation-related transcripts and chronic inflammation.
  • Hematopoiesis-specific Ythdf2 deficiency causes myeloid bias and lymphoid potential loss.
  • YTHDF2 protects HSCs against inflammation-induced damage.

Conclusions:

  • YTHDF2 acts as a repressor of inflammatory pathways in HSCs.
  • m6A modification mediated by YTHDF2 is critical for long-term HSC maintenance.
  • Dysregulation of YTHDF2 contributes to hematopoietic dysfunction and inflammation.