Human HSPCs clones balance stochastic diversification with cytokine-induced differentiation

Modern bone marrow atlases specify static transcriptional states, but not HSPC dynamics, which are only partly understood, particularly in humans. Here, we introduce cHSPCTrack (clonal HSPC tracker), an in vitro framework for serially tracking clonal differentiation and fate acquisition from human HSPCs extracted from circulation.

By following thousands of single-cell-derived clones stimulated by different cytokine combinations, cHSPCTrack reconstructs the balance between stochasticity and directed differentiation in human HSPCs. Single HSPCs stochastically yield multiple lineages under a uniform cytokine environment, with stimulatory inputs modulating differentiation probabilities by introducing biases toward preferred fates. In parallel, differentiation rates vary stochastically across and within clones.