Hematopoietic stem cell niche generation and maintenance are distinguishable by an epitranscriptomic program.

Area of Science:

• Stem cell biology
• Epigenetics
• Developmental biology

Background:

• The stem cell niche, crucial for stem cell function, is often viewed as a static structure.
• The molecular regulation governing the initial formation versus ongoing maintenance of stem cell niches is poorly understood.
• Mesenchymal stromal cells (MSCs) are key constituents of the hematopoietic stem cell (HSC) niche.

Purpose of the Study:

• To investigate whether distinct molecular mechanisms regulate the establishment and maintenance of the HSC niche.
• To compare the roles of m6A mRNA methylation in perinatal versus adult MSCs within the HSC niche.

Main Methods:

• Comparative analysis of perinatal and adult bone marrow MSCs.
• Investigated the expression and function of Mettl3 (an m6A methyltransferase) and its target Klf2 in MSCs.
• Utilized genetic deletion strategies (Mettl3, Klf2) in developing and adult MSCs and osteoblasts.
• Assessed HSC niche formation and osteogenic differentiation.

Main Results:

• Perinatal MSCs show enrichment in genes related to m6A mRNA methylation, with Mettl3 expression downregulated post-birth.
• Mettl3 deletion in developing MSCs impairs HSC niche formation and promotes osteogenic differentiation.
• Klf2 deletion rescues the HSC niche defect caused by Mettl3 deletion in developing MSCs.
• Mettl3 deletion in postnatal MSCs does not impact the HSC niche.

Conclusions:

• Stem cell niche generation and maintenance are controlled by distinct molecular mechanisms.
• m6A mRNA methylation, specifically Mettl3 activity in developing MSCs, is critical for HSC niche establishment.
• These findings offer potential targets for regenerative medicine strategies aimed at modulating stem cell niches.