Publication date: Jun 18, 2026
Human pluripotent stem cells (hPSCs) can be used as a scalable source of lymphocytes for adoptive cell therapies, contingent on the robust generation of definitive hematopoietic intermediates. Early WNT activation with CHIR99021 during mesoderm induction promoted the formation of KDR+ ALDH1A2+ mesoderm, which is essential for subsequent generation of T cells in a retinoic acid (RA)-dependent manner. Integrated scRNA-seq and ATAC-seq defined a WNT-dependent developmental trajectory from hPSCs to KDR+ ALDH1A2+ mesoderm. Gene regulatory network modeling predicted HDAC2 and E-box transcription factors as regulators of RA-responsive mesodermal differentiation downstream of WNT. HDAC2 knockout impaired, while HDAC2 overexpression enhanced KDR+ ALDH1A2+ mesoderm formation. E-box factor manipulation had no discernible effect. An orthogonal chemical screen confirmed that HDAC2 inhibition suppressed KDR+ ALDH1A2+ mesoderm, whereas modulating histone methylation enhanced their formation. These findings reveal mechanisms by which WNT signaling promotes RA-responsive mesoderm, and they suggest methods to improve the generation of lymphocytes from hPSCs.
| Concepts | Keywords |
|---|---|
| Aldh1a2 | epigenetics |
| Downstream | hematopoiesis |
| Hematopoietic | lymphopoiesis |
| Modeling | mesoderm |
| Overexpression | pluripotent stem cells |
| transcription | |
| WNT signaling |
Semantics
| Type | Source | Name |
|---|---|---|
| drug | DRUGBANK | Tretinoin |
| pathway | REACTOME | Methylation |