Host cell competition is a major barrier to engraftment following in utero hematopoietic cell transplantation (IUHCT). Here we describe a cell-engineering strategy using glycogen synthase kinase-3 (GSK3) inhibitor-loaded nanoparticles conjugated to the surface of donor hematopoietic cells in order to enhance their proliferation kinetics and ability to compete against their fetal host equivalents. With this approach, we achieved remarkable levels of stable, long-term hematopoietic engraftment for up to 24 weeks post IUHCT. We also show that the salutary effects of nanoparticle-released GSK3 inhibitor are specific to donor progenitor/stem cells, and are achieved by a pseudo-autocrine mechanism. These results establish that IUHCT of hematopoietic cells decorated with GSK3 inhibitor-loaded nanoparticles can produce therapeutic levels of long-term engraftment and could therefore allow single-step prenatal treatment of congenital hematological disorders.

中文翻译：

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带有 GSK3 抑制剂纳米颗粒的供体细胞工程增强了子宫移植后的植入

宿主细胞竞争是子宫内造血细胞移植 (IUHCT) 后移植的主要障碍。在这里，我们描述了一种细胞工程策略，该策略使用载有糖原合酶激酶 3 (GSK3) 抑制剂的纳米颗粒与供体造血细胞表面结合，以增强其增殖动力学和与其胎儿宿主等价物竞争的能力。通过这种方法，我们在 IUHCT 后长达 24 周内实现了显着水平的稳定、长期造血移植。我们还表明，纳米颗粒释放的 GSK3 抑制剂的有益作用对供体祖细胞/干细胞具有特异性，并且是通过假自分泌机制实现的。