CSF1R-dependent macrophages control postnatal somatic growth and organ maturation

Area of Science:

• Immunology and Developmental Biology
• Macrophage Biology
• Genetics and Genomics

Background:

• Homozygous mutation of the Csf1r locus (Csf1rko) results in severe postnatal developmental abnormalities.
• Csf1r is essential for the development and survival of macrophages.
• Understanding Csf1r function is critical for deciphering macrophage roles in development and homeostasis.

Purpose of the Study:

• To investigate the mechanisms underlying Csf1r mutation-induced developmental abnormalities.
• To characterize the phenotype of Csf1rko rats, focusing on early postnatal development and organ systems.
• To determine the cellular origin of the Csf1rko phenotype and identify potential therapeutic interventions.

Main Methods:

• Generation of Csf1rko rats on a Dark Agouti background with a Csf1r-mApple reporter transgene.
• Phenotypic analysis of Csf1rko rats, including musculoskeletal development, organ morphology, and gene expression profiling (liver).
• Bone marrow (BM) transplantation experiments from wild-type (WT) to Csf1rko recipients.

Main Results:

• Csf1rko led to near-complete loss of embryonic and adult tissue macrophages, impacting multiple organs and musculoskeletal development.
• Gene expression profiling revealed significant alterations in liver metabolism, hepatocyte maturation, and the IGF1 system in Csf1rko rats.
• WT BM transplantation rescued macrophage populations, reversed developmental abnormalities, restored organ function, and enabled long-term survival and fertility.

Conclusions:

• The Csf1rko phenotype is autonomous to bone marrow-derived cells, highlighting the critical role of Csf1r-dependent macrophages.
• Bone marrow transplantation demonstrates the potential for therapeutic intervention in Csf1r-related developmental disorders.
• The study suggests the existence of a distinct progenitor for tissue macrophages within the bone marrow, separate from hematopoietic stem cells.