Human HSPCs clones balance stochastic diversification with cytokine-induced differentiation

Area of Science:

• Hematology
• Stem Cell Biology
• Developmental Biology

Background:

• Hematopoietic stem and progenitor cells (HSPCs) are crucial for blood cell production, balancing self-renewal and differentiation.
• Current understanding of human HSPC dynamics and clonal differentiation is limited, with existing atlases showing static states.

Purpose of the Study:

• To develop and utilize an in vitro framework, cHSPCTrack, for tracking clonal differentiation and fate acquisition from human HSPCs.
• To investigate the balance between stochasticity and directed differentiation in human HSPCs under varying cytokine conditions.

Main Methods:

• Developed cHSPCTrack, an in vitro system for serial tracking of single-cell-derived HSPC clones.
• Stimulated thousands of clones with different cytokine combinations to observe differentiation trajectories.
• Analyzed clonal differentiation patterns, gene expression memory, and interactions between cell fates within clones.

Main Results:

• Human HSPCs exhibit stochastic differentiation into multiple lineages, with cytokine signals introducing biases toward specific fates.
• Differentiation rates show stochastic variation across and within clones.
• Clonal memory influences gene induction, and multiple cell fates can co-exist within a single clone, such as basophils, eosinophils, and mast cells.

Conclusions:

• cHSPCTrack provides a novel framework for dissecting human HSPC clonal dynamics.
• Findings illuminate the interplay of stochasticity, directed differentiation, and clonal memory in hematopoiesis.
• This approach has implications for understanding hematopoietic disorders and developing targeted therapies.