Local oxygen tension dictates hematopoietic cell growth and potency

Area of Science:

• Hematology
• Cell Biology
• Biochemistry

Background:

• Hematopoietic stem and progenitor cells (HSPCs) are crucial for lifelong blood production and serve as a key cell therapy platform for hematologic disorders.
• Understanding the environmental factors influencing HSPC function, particularly oxygen levels, is vital for optimizing cell therapies.

Purpose of the Study:

• To define the oxygen-dependent activities of HSPCs.
• To investigate how varying oxygen concentrations affect the expansion, maintenance, and potency of different HSPC populations.
• To identify molecular pathways and biomarkers associated with oxygen-dependent HSPC behavior.

Main Methods:

• Comparative analysis of HSPC expansion and frequency under high versus low oxygen conditions using cells from umbilical cord blood, bone marrow, and mobilized peripheral blood.
• Single-cell transcriptomic profiling of hematopoiesis across different oxygen levels.
• Biochemical validation of identified molecular pathways and biomarkers.

Main Results:

• Lineage-defined progenitor cells expanded more in high oxygen, whereas primitive HSPCs, including those with in vivo potency, were better maintained in low physiologic oxygen (O2).
• Transcriptomic analysis revealed modulation of hypoxia programs (HIF, MTORc) and identified understudied pathways (MDM4) and a novel biomarker (PRSS2) for hematopoietic cell potency.
• Low oxygen preserves less metabolically active, less proliferative cells with reduced stress markers, likely through a dynamic interplay of molecular programs.

Conclusions:

• Oxygen levels significantly influence HSPC behavior, impacting their expansion, maintenance, and potency.
• Oxygen-sensing pathways represent promising targets for improving HSPC expansion and function in cell therapies.
• Local oxygenation within anatomic niches plays a critical role in dictating hematopoietic potential.