Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
Cell Stem Cell. 2023 Apr 6;30(4):378-395.e8. doi: 10.1016/j.stem.2023.03.005.
Hematopoietic stem cell (HSC) self-renewal and aging are tightly regulated by paracrine factors from the bone marrow niche. However, whether HSC rejuvenation could be achieved by engineering a bone marrow niche ex vivo remains unknown. Here, we show that matrix stiffness fine-tunes HSC niche factor expression by bone marrow stromal cells (BMSCs). Increased stiffness activates Yap/Taz signaling to promote BMSC expansion upon 2D culture, which is largely reversed by 3D culture in soft gelatin methacrylate hydrogels. Notably, 3D co-culture with BMSCs promotes HSC maintenance and lymphopoiesis, reverses aging hallmarks of HSCs, and restores their long-term multilineage reconstitution capacity. In situ atomic force microscopy analysis reveals that mouse bone marrow stiffens with age, which correlates with a compromised HSC niche. Taken together, this study highlights the biomechanical regulation of the HSC niche by BMSCs, which could be harnessed to engineer a soft bone marrow niche for HSC rejuvenation.
造血干细胞（HSC）的自我更新和衰老受到骨髓龛中旁分泌因子的严格调控。然而，通过工程化构建体外骨髓龛来实现 HSC 年轻化是否可行仍不清楚。本研究表明，基质硬度通过骨髓基质细胞（BMSC）精细调节 HSC 龛因子的表达。在二维培养中，增加硬度会激活 Yap/Taz 信号通路，促进 BMSC 扩增，而在软明胶甲基丙烯酸酯水凝胶中的三维培养中，这种扩增会被很大程度逆转。值得注意的是，与 BMSC 进行三维共培养可促进 HSC 的维持和淋巴生成，逆转 HSC 的衰老特征，并恢复其长期多谱系重建能力。原位原子力显微镜分析显示，随着年龄的增长，小鼠骨髓变硬，这与 HSC 龛位受损有关。综上所述，本研究强调了 BMSC 对 HSC 龛位的生物力学调节，这可能有助于工程化构建柔软的 HSC 龛位以实现 HSC 年轻化。
