Ascorbate regulates haematopoietic stem cell function and leukaemogenesis.

Area of Science:

• Biochemistry
• Cell Biology
• Hematology

Background:

• Stem-cell fate is influenced by metabolites in culture.
• Regulation of stem-cell function by physiological metabolite variations in vivo remains unclear.

Purpose of the Study:

• To investigate the role of physiological metabolite variations in regulating stem-cell function in vivo.
• To develop a metabolomics method for analyzing rare cell populations directly from tissues.

Main Methods:

• Developed a novel metabolomics method for rare cell population analysis.
• Compared metabolic signatures of mouse hematopoietic stem cells (HSCs) and progenitors.
• Investigated the effects of systemic ascorbate depletion on HSCs in mice.

Main Results:

• Distinct metabolic signatures were identified for each hematopoietic cell type.
• HSCs exhibited high ascorbate levels, decreasing with differentiation.
• Ascorbate depletion increased HSC frequency and function, partly by inhibiting the tumor suppressor Tet2.
• Ascorbate depletion accelerated Flt3-mutated leukemogenesis, an effect reversed by dietary ascorbate.

Conclusions:

• Ascorbate accumulation in HSCs promotes Tet activity, limiting HSC frequency and suppressing leukemogenesis.
• Ascorbate negatively regulates HSC function and myelopoiesis via Tet2-dependent and independent mechanisms.
• Metabolite levels, specifically ascorbate, play a crucial role in regulating stem-cell function and preventing leukemia in vivo.