Efficient chemical reprogramming of human T cells into functional megakaryocytes and platelets

Abstract

The generation of megakaryocytes (MKs) from human somatic cells through chemical reprogramming represents a promising strategy for developing alternative platelet sources. Building on our prior chemical reprogramming protocol for converting erythroblasts to MKs, we established a robust method that successfully generated induced MKs (iMKs) from human cord blood–derived CD3+ T cells, which is a more abundant source. This method used a five–small molecule cocktail containing a reprogramming booster, AZD4205, to promote erasure of T cell identity and facilitate fate transition toward MKs. T cell–derived iMKs exhibited characteristic MK cellular and molecular signatures, demonstrating the capacity to produce proplatelets and release functional platelets. Single-cell RNA sequencing further revealed that iMKs were heterogeneous with distinct functional profiles, including cycling, immune, and thrombopoiesis-biased MKs. Our findings highlight an optimized chemical reprogramming strategy that enables efficient conversion of T cells to MKs, providing a practical and convenient approach to generating clinically relevant MKs and platelets.