Competition between hematopoietic stem and progenitor cells controls hematopoietic stem cell compartment size

Area of Science:

• Hematology
• Stem Cell Biology
• Cellular Competition

Background:

• Cellular competition for limited factors is crucial for regulating hematopoietic stem cells (HSCs).
• The precise mechanisms governing this competition, particularly involving mesenchymal stem/progenitor cells (MSPCs) and endothelial cells (ECs), remain unclear.

Purpose of the Study:

• To investigate the role of hematopoietic progenitor interaction with MSPCs and ECs in regulating HSC numbers.
• To elucidate the molecular mechanisms underlying cellular competition in hematopoiesis.

Main Methods:

• Disrupting hematopoietic progenitor access to Leptin receptor-expressing MSPCs and ECs.
• Analyzing HSC numbers and progenitor cell responses to chemokines like CXCL12.
• Assessing the expression of CXCR4 on hematopoietic progenitors and cKit on progenitors and mature cells.
• Evaluating the availability of membrane-bound stem cell factor (mSCF) on MSPCs and ECs.

Main Results:

• HSC numbers doubled when early hematopoietic progenitors lost responsiveness to CXCL12 from MSPCs and ECs.
• HSC expansion was dependent on early progenitors, not differentiated cells, lacking CXCR4.
• MSPC and EC transcriptomic profiles remained stable despite altered progenitor interactions.
• HSC expansion correlated with increased mSCF availability, likely due to reduced consumption by cKit-expressing progenitors.

Conclusions:

• Cellular competition for limited mSCF between HSCs and proximal hematopoietic progenitors is a key regulator of hematopoietic homeostasis.
• Disruption of progenitor cell signaling pathways, such as CXCL12/CXCR4, can lead to HSC expansion.
• MSPCs and ECs play a critical role in modulating HSC numbers through the provision of essential factors like mSCF.