A bifurcation concept for B-lymphoid/plasmacytoid dendritic cells with largely fluctuating transcriptome dynamics

Area of Science:

• Immunology
• Computational Biology
• Developmental Biology

Background:

• Hematopoiesis was traditionally viewed as stepwise but revised to continuous with single-cell RNA sequencing.
• The role of transcriptome dynamics and fluctuations in cell differentiation, particularly for dendritic cells (DCs), remains unclear.

Purpose of the Study:

• To investigate the B/plasmacytoid dendritic cell (pDC) bifurcation and associated transcriptome dynamics.
• To develop a computational model that incorporates fluctuations in cell differentiation.

Main Methods:

• Utilized both computational (dry) and experimental (wet) methods.
• Developed a deep generative model converting splicing kinetics into diffusion dynamics.
• Employed a niche-like culture system for progenitor cells.

Main Results:

• Identified large transcriptome fluctuations at the B/pDC bifurcation in IL-7Rα+ progenitor regions.
• Observed positive fluctuation of LFA-1 expression towards the pDC lineage at the bifurcation.
• Validated the presence of B/pDC progenitors and preferential LFA-1 expression in pDC-biased progenitors.

Conclusions:

• Proposed a novel fluctuation-based model of cell differentiation.
• Reconciled continuous and discrete models of development.
• Demonstrated the model's applicability to other developmental systems.