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Fibrillin-1 microfibrils influence adult bone marrow hematopoiesis

Silvia Smaldone1, Carolina L Bigarella2, Maria Del Solar1

  • 1Department of Pharmacology and Systems Therapeutics and Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029.

Matrix Biology : Journal of the International Society for Matrix Biology
|November 28, 2015
PubMed

Insights

Fibrillin-1 restricts red blood cell production and promotes hematopoietic stem cell expansion. This extracellular matrix protein’s role in adult hematopoiesis is linked to TGFβ modulation in bone marrow niches.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Developmental Biology

Background:

  • Fibrillin-1 regulates mesenchymal stem cell (MSC) fate by modulating TGFβ activity.
  • MSCs influence hematopoietic stem cell (HSC) activities, impacting adult hematopoiesis.

Purpose of the Study:

  • Investigate the role of fibrillin-1 in adult hematopoiesis using a mouse model with targeted gene inactivation.
  • Determine how fibrillin-1 deficiency affects HSCs, erythropoiesis, and myeloid progenitor cells.

Main Methods:

  • Cre-mediated inactivation of the fibrillin-1 (Fbn1) gene in mesenchymal cells (Fbn1(Prx1-/-) mice).
  • Analysis of peripheral blood cells, erythropoiesis, HSC frequency, and myeloid progenitor cells via flow cytometry and differentiation assays.
  • Systemic treatment with TGF-β-neutralizing antibodies in mutant and wild-type mice.

Main Results:

  • Fbn1(Prx1-/-) mice exhibited increased circulating red blood cells and augmented erythropoiesis, indicating fibrillin-1 restricts erythroid progenitor differentiation.
  • A decreased HSC frequency was observed in Fbn1(Prx1-/-) mice, suggesting fibrillin-1 promotes HSC expansion.
  • No significant differences in myeloid progenitor cell abundance or differentiation potential were found between mutant and wild-type mice.
  • TGF-β modulation differed between HSC and erythroid niches, as evidenced by differential outcomes of antibody treatments.

Conclusions:

  • Fibrillin-1 plays a crucial role in regulating adult hematopoiesis by promoting HSC expansion and restricting erythroid differentiation.
  • The extracellular matrix protein fibrillin-1 differentially modulates TGFβ activity in HSC and erythroid niches.
  • Targeting fibrillin-1 and TGFβ pathways may offer therapeutic strategies for hematological disorders.
Keywords:
ErythropoiesisFibrillin-1HematopoiesisMarrow stem cellsTGFβ

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