Department of Biomedical Engineering, Tulane University, New Orleans, Louisiana, United States of America.
RoosterBio Inc., Frederick, Maryland, United States of America.
PLoS One. 2018 Apr 17;13(4):e0195588. doi: 10.1371/journal.pone.0195588. eCollection 2018.
Use of stem cell-based therapies in tissue engineering and regenerative medicine is hindered by efficient means of directed differentiation. For pluripotent stem cells, an initial critical differentiation event is specification to one of three germ lineages: endoderm, mesoderm, and ectoderm. Differentiation is known to be regulated by numerous extracellular and intracellular factors, but the role of the cytoskeleton during specification, or early differentiation, is still unknown. In these studies, we used agonists and antagonists to modulate actin polymerization and the actin-myosin molecular motor during spontaneous differentiation of embryonic stem cells in embryoid bodies. We found that inhibiting either actin polymerization or actin-myosin interactions led to a decrease in differentiation to the mesodermal lineage and an increase in differentiation to the endodermal lineage. Thus, targeting processes that regulate cytoskeletal tension may be effective in enhancing or inhibiting differentiation towards cells of the endodermal or mesodermal lineages, which include hepatocytes, islets, cardiomyocytes, endothelial cells, and osteocytes. Therefore, these fundamental findings demonstrate that modulation of the cytoskeleton may be useful in production for a range of cell-based therapies, including for liver, pancreatic, cardiac, vascular, and orthopedic applications.
基于干细胞的疗法在组织工程和再生医学中的应用受到有效定向分化方法的阻碍。对于多能干细胞，最初的关键分化事件是指定到三个生殖系之一：内胚层、中胚层和外胚层。分化已知受许多细胞外和细胞内因素的调节，但在指定或早期分化过程中细胞骨架的作用仍然未知。在这些研究中，我们使用激动剂和拮抗剂在胚胎干细胞自发分化为胚状体时调节肌动蛋白聚合和肌动球蛋白分子马达。我们发现，抑制肌动蛋白聚合或肌动球蛋白相互作用会导致向中胚层谱系的分化减少，而向内胚层谱系的分化增加。因此，针对调节细胞骨架张力的过程可能有效增强或抑制向包括肝细胞、胰岛、心肌细胞、内皮细胞和成骨细胞在内的内胚层或中胚层谱系的分化。因此，这些基础发现表明，细胞骨架的调节可能对一系列基于细胞的治疗方法的生产有用，包括用于肝脏、胰腺、心脏、血管和骨科应用。
