Single-Cell Proteo-Transcriptomic Profiling Uncovers Post-Translational Regulatory Layers in Human Hematopoiesis
Year: 2026
Type: preprint
Abstract: Background Hematopoietic stem cells (HSCs) have the unique ability to produce all mature cell types in the blood and understanding the mechanisms governing their differentiation and renewal is a driving question in stem cell biology. While single-cell RNA sequencing has transformed our view of human hematopoiesis, mRNA abundance represents an incomplete proxy for functional cell states. Here, we apply single-cell multimodal profiling to simultaneously measure 280 surface and intracellular protein targets alongside whole transcriptomes within individual adult human hematopoietic stem and progenitor cells. Results By directly coupling modalities within single cells, we show that protein-RNA correlations peak dynamically in transitioning intermediate progenitors across lineages, consistent with pervasive post-transcriptional mechanics underlying lineage choice. Furthermore, key transcription factor proteins maintain multilineage co-expression longer into commitment than their transcripts, demarcating a possible window of fate decision reversibility. Moreover, low and flat CTNNB1 mRNA levels mask late-erythroid β-catenin protein enrichment, apparently pairing with E-cadherin expression and suggesting post-translational stabilization at the cell membrane. Conclusions This dataset enables the observation of translational dynamics and RNA-protein relationships throughout the differentiation landscape at an unprecedented level of granularity. Together, our findings demonstrate that transcriptomics alone misses fundamental regulatory programs, establishing single-cell proteo-transcriptomics as a powerful tool for decoding human stem cell fate.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: Defining the Haematopoietic System through Integrated Multi-Scale Analysis, G2179809317, Defining the Haematopoietic System through Integrated Multi-Scale Analysis, G3187034290, Haematopoiesis in a Dish: From Tissue Dynamics to Molecular Mechanisms, Characterization of inflammation driven responses in human hematopoietic stem and progenitor cells., Haematopoiesis across Scales, Species and Time: a Foundational Approach to Study Stem Cell Biology and Disease, UK Human Developmental Biology Initiative, UK Human Developmental Biology Initiative, Characterization of inflammation driven responses in human hematopoietic stem and progenitor cells.
OpenAlex ID: W7221577398