1 Translational and Stem Cell Research Laboratory on Stroke, Sungkyunkwan University, Jongno-gu, Seoul, South Korea.
2 Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Gangnam-gu, Seoul, South Korea.
Cell Transplant. 2018 Mar;27(3):485-500. doi: 10.1177/0963689718755404. Epub 2018 May 18.
Stroke induces complex and dynamic, local and systemic changes including inflammatory reactions, immune responses, and repair and recovery processes. Mesenchymal stem cells (MSCs) have been shown to enhance neurological recovery after stroke. We hypothesized that serum factors play a critical role in the activation of bone marrow (BM) MSCs after stroke such as by increasing proliferation, paracrine effects, and rejuvenation. Human MSCs (hMSCs) were grown in fetal bovine serum (FBS), normal healthy control serum (NS), or stroke patient serum (SS). MSCs cultured in growth medium with 10% SS or NS exhibited higher proliferation indices than those cultured with FBS ( P < 0.01). FBS-, NS-, and SS-hMSCs showed differences in the expression of trophic factors; vascular endothelial growth factor, glial cell-derived neurotrophic factor, and fibroblast growth factor were densely expressed in samples cultured with SS ( P < 0.01). In addition, SS-MSCs revealed different cell cycle- or aging-associated messenger RNA expression in a later passage, and β-galactosidase staining showed the senescence of MSCs observed during culture expansion was lower in MSCs cultured with SS than those cultured with NS or FBS ( P < 0.01). Several proteins related to the activity of receptors, growth factors, and cytokines were more prevalent in the serum of stroke patients than in that of normal subjects. Neurogenesis and angiogenesis were markedly increased in rats that had received SS-MSCs ( P < 0.05), and these rats showed significant behavioral improvements ( P < 0.01). Our results indicate that stroke induces a process of recovery via the activation of MSCs. Culture methods for MSCs using SS obtained during the acute phase of a stroke could constitute a novel MSC activation method that is feasible and efficient for the neurorestoration of stroke.
中风会引起复杂而动态的局部和全身变化，包括炎症反应、免疫反应以及修复和恢复过程。间充质干细胞（MSCs）已被证明可以促进中风后的神经恢复。我们假设，血清因子在中风后骨髓（BM）MSCs的激活中起着关键作用，例如通过增加增殖、旁分泌作用和恢复活力。将人 MSCs（hMSCs）在胎牛血清（FBS）、正常健康对照血清（NS）或中风患者血清（SS）中培养。在含有 10%SS 或 NS 的生长培养基中培养的 MSCs 的增殖指数高于在 FBS 中培养的 MSCs（P<0.01）。FBS、NS 和 SS-hMSCs 表达的营养因子存在差异；在 SS 培养的样本中，血管内皮生长因子、胶质细胞源性神经营养因子和成纤维细胞生长因子表达密集（P<0.01）。此外，SS-MSCs 在后期传代中表现出不同的细胞周期或衰老相关信使 RNA 表达，β-半乳糖苷酶染色显示，在 SS 培养的 MSC 中观察到的培养扩增过程中的 MSC 衰老程度低于在 NS 或 FBS 中培养的 MSC（P<0.01）。与受体、生长因子和细胞因子的活性相关的几种蛋白质在中风患者的血清中比在正常受试者的血清中更为普遍。在接受 SS-MSCs 的大鼠中，神经发生和血管生成明显增加（P<0.05），这些大鼠表现出显著的行为改善（P<0.01）。我们的结果表明，中风通过激活 MSCs 来诱导恢复过程。在中风急性期使用 SS 进行 MSC 培养的方法可能构成一种新的 MSC 激活方法，对于中风的神经恢复是可行且有效的。
