García-Sánchez Daniel, González-González Alberto, García-García Patricia, Reyes Ricardo, Pérez-Núñez María Isabel, Riancho José A, Évora Carmen, Rodríguez-Rey José Carlos, Pérez-Campo Flor M
Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Cantabria-IDIVAL, 39012 Santander, Spain.
Department of Chemical Engineering and Pharmaceutical Technology, Institute of Biomedical Technologies (ITB), University of La Laguna, 38206 La Laguna, Spain.
Pharmaceutics. 2021 Aug 17;13(8):1277. doi: 10.3390/pharmaceutics13081277.
Mesenchymal stem cell (MSC) transplantation has emerged as a promising approach for bone regeneration. Importantly, the beneficial effects of MSCs can be improved by modulating the expression levels of specific genes to stimulate MSC osteogenic differentiation. We have previously shown that silencing by using Locked Nucleic Acid-Antisense Oligonucleotides, in combination with a scaffold that sustainably releases low doses of BMP-2, was able to increase the osteogenic potential of MSCs in the presence of BMP-2 doses significantly smaller than those currently used in the clinic. This would potentially allow an important reduction in this protein in MSs-based treatments, and thus of the side effects linked to its administration. We have further improved this system by specifically targeting the Wnt pathway modulator . This approach not only increases MSC bone regeneration efficiency, but is also able to induce osteogenic differentiation in osteoporotic human MSCs, bypassing the need for BMP-2 induction, underscoring the regenerative potential of this system. Achieving successful osteogenesis with the sole use of LNA-ASOs, without the need of administering pro-osteogenic factors such as BMP-2, would not only reduce the cost of treatments, but would also open the possibility of targeting these LNA-ASOs specifically to MSCs in the bone marrow, allowing us to treat systemic bone loss such as that associated with osteoporosis.
间充质干细胞(MSC)移植已成为一种有前景的骨再生方法。重要的是,通过调节特定基因的表达水平以刺激MSC成骨分化,可以增强MSC的有益作用。我们之前已经表明,使用锁核酸反义寡核苷酸进行沉默,结合可持续释放低剂量BMP-2的支架,能够在BMP-2剂量显著低于目前临床使用剂量的情况下提高MSC的成骨潜力。这可能会使基于MSC的治疗中该蛋白的用量大幅减少,从而降低与其给药相关的副作用。我们通过特异性靶向Wnt信号通路调节剂进一步改进了该系统。这种方法不仅提高了MSC骨再生效率,还能够在骨质疏松的人MSC中诱导成骨分化,无需BMP-2诱导,突出了该系统的再生潜力。仅使用LNA-ASO就能成功实现成骨,而无需施用诸如BMP-2等促骨生成因子,这不仅会降低治疗成本,还将开启将这些LNA-ASO特异性靶向骨髓中MSC的可能性,使我们能够治疗全身性骨质流失,如与骨质疏松症相关的骨质流失。