Blood Podcast CAR-iNKT cell immunotherapy and Jagged2/Notch regulation of HSC
Feb 12, 2026
Anastasios Karadimitris, a clinician-scientist developing invariant NKT cell immunotherapies, and Maria Carolina Florian, a researcher on hematopoietic stem cell aging, discuss cutting-edge science. They cover off-the-shelf dual CAR-iNKT cells targeting CD19 and CD133 and how Jagged2/Notch signaling flips from trans-activation to cis-inhibition to drive HSC aging. Short, focused conversations on therapy design and stem cell niche mechanisms.
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Notch Activity Marks Inactive Clustered Aged HSCs
- Notch signaling decreases after birth but resurges in aged HSCs as an inactive state marker.
- Using 3D imaging and a Notch-GFP reporter, Maria Carolina Florian showed aged HSCs cluster, become inactive, and expand with myeloid bias.
Jagged2 Loss Recreates HSC Aging Phenotype
- Endothelial Jagged2 loss in the niche is sufficient to reduce Notch activity and reproduce aging HSC phenotypes.
- Florian used a Jagged2 knockout in bone marrow vasculature to induce HSC cluster expansion and functional decline in mice.
Aged HSCs Switch Notch From Trans Activation To Cis Inhibition
- A trans-activation to cis-inhibition switch occurs when aged HSCs ectopically express Jagged2, turning off their own Notch signaling.
- This self-expressed Jagged2 preserves quiescence embryonically but becomes maladaptive in aging, reducing regenerative potential in transplantation assays.