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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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Notch signaling was first discovered in Drosophila melanogaster, where it is involved in cell lineage differentiation. Notch signaling regulates the maintenance and differentiation of intestinal stem cells or ISCs by controlling the expression of atonal homolog 1 or Atoh1. Atoh1 directs cells to differentiate into secretory cells.
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Mesenchymal stem cells (MSCs) are adult stem cells that can differentiate into most connective tissue cell types, except for hematopoietic cells, depending upon the source of MSCs. For example, bone-marrow-derived MSCs (BM-MSCs) can differentiate into osteocytes, hepatocytes, and pancreatic and neuronal cells. MSCs can be isolated from various sources such as bone marrow, placenta, adipose tissue, teeth, and Wharton’s jelly, a gelatinous substance in the umbilical cord. The ease of their...
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The stem cell niche is the dynamic microenvironment where stem cells reside. Inside these niches, the cells may remain undifferentiated, undergo high self-renewal, or become lineage-specific progenitors. Stem cells coexist with other niche cells, such as stromal cells. They also interact closely with the ECM. Cell-cell and cell-matrix communication occur via adhesion molecules or soluble factors that signal the stem cells and determine their fate. Stromal cells also provide survival signals to...
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Pan-myeloid Differentiation of Human Cord Blood Derived CD34+ Hematopoietic Stem and Progenitor Cells
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BAG3 regulates bone marrow mesenchymal stem cell proliferation by targeting INTS7.

Yubo Liu1, Renjie Xu1, Jinfu Xu2

  • 1Department of Orthopaedics, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China.

Peerj
|August 14, 2023
PubMed
Summary

Bone marrow mesenchymal stem cell (BMMSC) expansion is promoted by the protein BAG3, which directly interacts with INTS7. BAG3 reduces oxidative stress, enhancing BMMSC proliferation and survival.

Keywords:
BAG3BMMSCsINTS7Oxidative stress

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Area of Science:

  • Stem Cell Biology
  • Molecular Biology
  • Cellular Physiology

Background:

  • Bone marrow mesenchymal stem cells (BMMSCs) are crucial for tissue repair and regeneration.
  • BAG3 protein is known to regulate cell survival and has been implicated in cancer and heart disease.
  • Previous research suggested a potential interaction between BAG3 and INTS7 influencing BMMSC proliferation, but the direct binding and regulatory mechanisms remained unclear.

Purpose of the Study:

  • To elucidate the direct interaction between BAG3 and INTS7.
  • To determine the role of BAG3 in regulating bone marrow mesenchymal stem cell (BMMSC) proliferation and expansion.
  • To investigate the underlying molecular mechanisms by which BAG3 influences BMMSC behavior.

Main Methods:

  • Quantitative real-time PCR to assess BAG3 expression after siRNA knockdown.
  • Cell proliferation assays (CCK-8, colony formation) to evaluate BMMSC growth.
  • Transwell migration, flow cytometry, and TUNEL assays to analyze migration, cell cycle, and apoptosis.
  • Co-immunoprecipitation, protein half-life assays, and western blotting to determine molecular interactions and mechanisms.

Main Results:

  • BAG3 knockdown significantly reduced BMMSC proliferation, migration, and colony formation, while inducing apoptosis and cell cycle arrest.
  • BAG3 directly interacts with INTS7, as confirmed by co-immunoprecipitation and bioinformatics analyses.
  • BAG3 downregulation led to decreased INTS7 expression, increased INTS7 ubiquitination, elevated reactive oxygen species, and DNA damage in BMMSCs.
  • Overexpression of BAG3 or INTS7, or the use of antioxidants, rescued the detrimental effects of BAG3 knockdown on BMMSCs.

Conclusions:

  • BAG3 directly binds to INTS7.
  • BAG3 promotes BMMSC expansion and survival by mitigating oxidative stress and DNA damage.
  • The BAG3-INTS7 interaction is a key regulatory axis for maintaining BMMSC function.