Jablonska Anna, Drela Katarzyna, Wojcik-Stanaszek Luiza, Janowski Miroslaw, Zalewska Teresa, Lukomska Barbara
NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
Department of Radiology and Radiological Science, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Mol Neurobiol. 2016 Nov;53(9):6413-6425. doi: 10.1007/s12035-015-9530-6. Epub 2015 Nov 25.
Stroke is the leading cause of severe disability, and lacunar stroke is related to cognitive decline and hemiparesis. There is no effective treatment for the majority of patients with stroke. Thus, stem cell-based regenerative medicine has drawn a growing body of attention due to the capabilities for trophic factor expression and neurogenesis enhancement. Moreover, it was shown in an experimental autoimmune encephalomyelitis (EAE) model that even short-lived stem cells can be therapeutic, and we have previously observed that phenomenon indirectly. Here, in a rat model of lacunar stroke, we investigated the molecular mechanisms underlying the positive therapeutic effects of short-lived human umbilical cord-blood-derived neural stem cells (HUCB-NSCs) through the distinct measurement of exogenous human and endogenous rat trophic factors. We have also evaluated neurogenesis and metalloproteinase activity as cellular components of therapeutic activity. As expected, we observed an increased proliferation and migration of progenitors, as well as metalloproteinase activity up to 14 days post transplantation. These changes were most prominent at the 7-day time point when we observed 30 % increases in the number of bromodeoxyuridine (BrdU)-positive cells in HUCB-NSC transplanted animals. The expression of human trophic factors was present until 7 days post transplantation, which correlated well with the survival of the human graft. For these 7 days, the level of messenger RNA (mRNA) in the analyzed trophic factors was from 300-fold for CNTF to 10,000-fold for IGF, much higher compared to constitutive expression in HUCB-NSCs in vitro. What is interesting is that there was no increase in the expression of rat trophic factors during the human graft survival, compared to that in non-transplanted animals. However, there was a prolongation of a period of increased trophic expression until 14 days post transplantation, while, in non-transplanted animals, there was a significant drop in rat trophic expression at that time point. We conclude that the positive therapeutic effect of short-lived stem cells may be related to the net increase in the amount of trophic factors (rat + human) until graft death and to the prolonged increase in rat trophic factor expression subsequently.
中风是导致严重残疾的主要原因，腔隙性中风与认知衰退和偏瘫有关。对于大多数中风患者而言，目前尚无有效的治疗方法。因此，基于干细胞的再生医学因具有表达营养因子和增强神经发生的能力而受到越来越多的关注。此外，在实验性自身免疫性脑脊髓炎（EAE）模型中发现，即使是短期存活的干细胞也具有治疗作用，我们之前也间接观察到了这一现象。在此，我们在腔隙性中风大鼠模型中，通过对外源人源和内源性大鼠营养因子进行不同测量，研究了短期存活的人脐带血源性神经干细胞（HUCB-NSCs）产生积极治疗效果的分子机制。我们还评估了神经发生和金属蛋白酶活性，将其作为治疗活性的细胞组成部分。正如预期的那样，我们观察到祖细胞的增殖和迁移增加，以及移植后14天内金属蛋白酶活性增强。这些变化在第7天时间点最为显著，此时我们观察到HUCB-NSC移植动物中溴脱氧尿苷（BrdU）阳性细胞数量增加了30%。人源营养因子的表达一直持续到移植后7天，这与人类移植物的存活情况密切相关。在这7天里，所分析的营养因子中信使核糖核酸（mRNA）水平从睫状神经营养因子（CNTF）的300倍到胰岛素样生长因子（IGF）的10000倍，与HUCB-NSCs在体外的组成性表达相比要高得多。有趣的是，与未移植动物相比，在人类移植物存活期间大鼠营养因子的表达没有增加。然而，营养因子表达增加的时期延长至移植后14天，而在未移植动物中，此时大鼠营养因子表达显著下降。我们得出结论，短期存活干细胞的积极治疗效果可能与移植物死亡前营养因子（大鼠+人源）总量的净增加以及随后大鼠营养因子表达的延长增加有关。
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