2. Academic Validation
  3. Notch and retinoic acid signals regulate macrophage formation from endocardium downstream of Nkx2-5

Notch and retinoic acid signals regulate macrophage formation from endocardium downstream of Nkx2-5

  • Nat Commun. 2023 Sep 5;14(1):5398. doi: 10.1038/s41467-023-41039-6.
Norika Liu 1 2,  Naofumi Kawahira 2,  Yasuhiro Nakashima 3,  Haruko Nakano 2,  Akiyasu Iwase 4,  Yasunobu Uchijima 4,  Mei Wang 1,  Sean M Wu 5,  Susumu Minamisawa 1,  Hiroki Kurihara 4,  Atsushi Nakano 6 7 8 9 10
Affiliations

Affiliations

  • 1 The Jikei University School of Medicine, Department of Cell Physiology, Tokyo, Japan.
  • 2 University of California Los Angeles, Department of Molecular Cell and Developmental Biology, Los Angeles, USA.
  • 3 Kyoto University, Department of Cardiovascular Medicine, Kyoto, Japan.
  • 4 University of Tokyo, Department of Physiological Chemistry and Metabolism, Tokyo, Japan.
  • 5 Stanford University, Cardiovascular Institute and Division of Cardiovascular Medicine, Department of Medicine, Stanford, USA.
  • 6 The Jikei University School of Medicine, Department of Cell Physiology, Tokyo, Japan. [email protected].
  • 7 University of California Los Angeles, Department of Molecular Cell and Developmental Biology, Los Angeles, USA. [email protected].
  • 8 University of California Los Angeles, David Geffen Department of Medicine, Division of Cardiology, Los Angeles, USA. [email protected].
  • 9 Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, USA. [email protected].
  • 10 Molecular Biology Institute, University of California, Los Angeles, Los Angeles, USA. [email protected].
PMID: 37669937 DOI: 10.1038/s41467-023-41039-6
Abstract

Hematopoietic progenitors are enriched in the endocardial cushion and contribute, in a Nkx2-5-dependent manner, to tissue macrophages required for the remodeling of cardiac valves and septa. However, little is known about the molecular mechanism of endocardial-hematopoietic transition. In the current study, we identified the regulatory network of endocardial hematopoiesis. Signal network analysis from scRNA-seq datasets revealed that genes in Notch and retinoic acid (RA) signaling are significantly downregulated in Nkx2-5-null endocardial cells. In vivo and ex vivo analyses validate that the Nkx2-5-Notch axis is essential for the generation of both hemogenic and cushion endocardial cells, and the suppression of RA signaling via Dhrs3 expression plays important roles in further differentiation into macrophages. Genetic ablation study revealed that these macrophages are essential in cardiac valve remodeling. In summary, the study demonstrates that the Nkx2-5/Notch/RA signaling plays a pivotal role in macrophage differentiation from hematopoietic progenitors.

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