Reprogramming somatic cells into megakaryocytes (MKs) would provide a promising source of platelets. However, using a pharmacological approach to generate human MKs from somatic cells remains an unmet challenge. Here, we report that a combination of four small molecules (4M) successfully converted human cord blood erythroblasts (EBs) into induced MKs (iMKs). The iMKs could produce proplatelets and release functional platelets, functionally resembling natural MKs. Reprogramming trajectory analysis revealed an efficient cell fate conversion of EBs into iMKs by 4M via the intermediate state of bipotent precursors. 4M induced chromatin remodeling and drove the transition of transcription factor (TF) regulatory network from key erythroid TFs to essential TFs for megakaryopoiesis, including FLI1 and MEIS1. These results demonstrate that the chemical reprogramming of cord blood EBs into iMKs provides a simple and efficient approach to generate MKs and platelets for clinical applications.

将体细胞重编程为巨核细胞 (MKs) 将提供有希望的血小板来源。然而，使用药理学方法从体细胞产生人类 MKs 仍然是一个未解决的挑战。在这里，我们报告了四种小分子 (4M) 的组合成功地将人脐带血红细胞 (EB) 转化为诱导 MK (iMK)。iMKs 可以产生前血小板并释放功能性血小板，在功能上类似于天然 MKs。重编程轨迹分析揭示了 4M 通过双能前体的中间状态将 EBs 有效地转化为 iMKs 的细胞命运。4M 诱导染色质重塑并推动转录因子 (TF) 调控网络从关键的红细胞 TF 转变为巨核细胞生成的必需 TF，包括FLI1和梅斯1。这些结果表明，将脐带血 EB 化学重编程为 iMK 提供了一种简单有效的方法来生成用于临床应用的 MK 和血小板。