OC 48.2 - Aging-Related Changes in Megakaryocyte Progenitors: Single-Cell Transcriptomics Study

Monday, June 24, 2024

15:00 – 15:15 ICT

Room: 211 A-D

Presenting Author(s)

Pratintip Lee, MD

Ph.D. candidate
Center for Molecular Cardiology, University of Zurich, Cantonal Hospital Baden, Switzerland
Baden Dättwil, Aargau, Switzerland

Co-Author(s)

Soheil Saeedi Saravi

Group leader
Center for Translational and Experimental Cardiology, University Hospital Zurich
Zurich, Zurich, Switzerland
MA

Meret Allemann

Ph.D. candidate
Center for Molecular Cardiology, University of Zurich, Cantonal Hospital Baden, Switzerland
Zurich, Zurich, Switzerland
CB

Carolina Balbi

Postdoctoral researcher
Center for Molecular Cardiology, University of Zurich, Cantonal Hospital Baden, Switzerland
Zurich, Zurich, Switzerland
TW

Tongtong Wang

Ph.D. candidate
Institute of Food, Nutrition and Health, ETH Zurich
Zurich, Zurich, Switzerland
CW

Christian Wolfrum

Prof. Dr.
Institute of Food, Nutrition and Health, ETH Zurich
Zurich, Zurich, Switzerland
JH

Jürg Hans Beer

Prof. Dr. Med
Center for Molecular Cardiology, University of Zurich, Cantonal Hospital Baden, Switzerland
Zurich, Zurich, Switzerland

Background: Platelet (Plt) hyperreactivity increases in aging and contributes to cardiovascular diseases (CVD) and thromboembolism (TE). Although different factors related to aging have been observed to influence plt, the exact origin of age-related changes in plt function is not fully understood.

Aims: We aimed to study the age-specific pro-thrombotic and pro-inflammatory characteristics of MkP in aged mice.

Methods: Single-cell RNAseq was conducted on bone marrow (BM) samples obtained from femora and tibiae of young (3 months) and aged (>24 months) male and female mice. Sorting was employed to enrich MkP from the BM. Cells were processed and sequenced using the 10x Genomics single-platform. MkP cells were transcriptionally defined by the highest expression of their specific genes including Pf4, Vwf, Gp6, Gp1ba, Itgb3, Mpl. Based on functional signatures derived from the Gene Ontology database, we performed enrichment pathway analyses in MkP clusters and compared the transcriptional signatures-base scores between aged and young.

Results: We identified 5 discrete clusters of MkPs (MkP1 to 5) (fig.1B-D). We observed important differences between aged and young mice, notably an increased proportion of MkP-3 subset in the aged group (fig.1E). Pathway enrichment analyses found enriched clusters of pro-immune-inflammatory and pro-thrombotic genes within MkP-3. Specifically, the MkP-3 clusters exhibited both higher T-cell activation, inflammatory, and cytokine scores along with increased plt activation and coagulation scores in the aged group (fig.2A-B). Interestingly, differential gene expression (DGE) analyses found that aged MkP displayed higher expression of T-cell regulated genes including Camk1d, Cd180, Cd226, Tgfb1 and Itga2 (fig.2C-E). Our findings may point to adaptive immune response as potential mechanism in aged-induced CVD and TE.

Conclusion(s): 1.Aging is associated with the upregulation of immune-related and pro-thrombotic MkP subsets within the BM.
2.Our findings can mechanistically explain the development of CVD and TE in the elderly, suggesting potential novel therapeutic targets.