Population dynamics modeling reveals myeloid bias involves both HSC differentiation and progenitor proliferation biases
Aging and chronic inflammation are associated with overabundant myeloid-primed multipotent progenitors (MPPs) amongst hematopoietic stem and progenitor cells (HSPCs).  While HSC differentiation bias has been considered a primary cause of myeloid bias, whether it is sufficient has not been quantitatively evaluated.  Here, we analyzed bone marrow data from the I?B– (Nfkbia+/-Nfkbib-/-Nfkbie-/-) mouse model of inflammation with elevated NF?B activity, which shows increased myeloid-biased MPPs.  We interpreted these data with differential equations models of population dynamics to identify alterations of HSPC proliferation and differentiation rates.  This analysis revealed that short-term (ST) HSC differentiation bias alone is likely insufficient to account for the increase in myeloid-biased MPPs.  To explore additional mechanisms, we used single-cell RNA sequencing (scRNA-seq) measurements of I?B– and wild-type HSPCs to track the continuous differentiation-trajectories from HSCs to erythrocyte/megakaryocyte, myeloid, and lymphoid primed progenitors.  Fitting a partial differential equations model of population dynamics to these data revealed not only less lymphoid-fate specification amongst HSCs, but also increased expansion of early myeloid-primed progenitors.  Differentially expressed genes along the differentiation-trajectories supported increased proliferation amongst these progenitors.  These findings were conserved when wild-type HSPCs were transplanted into I?B– recipients, indicating that an inflamed bone marrow microenvironment is a sufficient driver.  We then applied our analysis pipeline to published scRNA-seq measurements of HSPCs isolated from aged mice, as well as human myeloid neoplasm patients.  These analyses identified the same myeloid-primed progenitor expansion as in the I?B– models, suggesting that it is a common feature across different settings of myeloid bias. Overall design: Lin- Sca1+ cKitHi (LSK) HSPCs were isolated from the bone marrow of the bilateral femur and tibia by flow sorting, from young WT and I?B– mice, and analyzed by scRNA-seq.