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. 2021 Dec;99(12):1815-1827.
doi: 10.1007/s00109-021-02135-6. Epub 2021 Oct 11.

Intramyocardial injection of human adipose-derived stem cells ameliorates cognitive deficit by regulating oxidative stress-mediated hippocampal damage after myocardial infarction

Tsung-Ming Lee  1 , Cheng-Che Lee  2 , Horng-Jyh Harn  3 , Tzyy-Wen Chiou  4 , Ming-Hsi Chuang  5   6 , Chun-Hung Chen  6 , Chi-Hsuan Chuang  7 , Po-Cheng Lin  6 , Shinn-Zong Lin  8
Affiliations

Intramyocardial injection of human adipose-derived stem cells ameliorates cognitive deficit by regulating oxidative stress-mediated hippocampal damage after myocardial infarction

Tsung-Ming Lee et al. J Mol Med (Berl). 2021 Dec.

Abstract

Cognitive impairment is a serious side effect of post-myocardial infarction (MI) course. We have recently demonstrated that human adipose-derived stem cells (hADSCs) ameliorated myocardial injury after MI by attenuating reactive oxygen species (ROS) levels. Here, we studied whether the beneficial effects of intramyocardial hADSC transplantation can extend to the brain and how they may attenuate cognitive dysfunction via modulating ROS after MI. After coronary ligation, male Wistar rats were randomized via an intramyocardial route to receive either vehicle, hADSC transplantation (1 × 106 cells), or the combination of hADSCs and 3-Morpholinosydnonimine (SIN-1, a peroxynitrite donor). Whether hADSCs migrated into the hippocampus was assessed by using human-specific primers in qPCR reactions. Passive avoidance test was used to assess cognitive performance. Postinfarction was associated with increased oxidative stress in the myocardium, circulation, and hippocampus. This was coupled with decreased numbers of dendritic spines as well as a significant downregulation of synaptic plasticity consisting of synaptophysin and PSD95. Step-through latency during passive avoidance test was impaired in vehicle-treated rats after MI. Intramyocardial hADSC injection exerted therapeutic benefits in improving cardiac function and cognitive impairment. None of hADSCs was detected in rat's hippocampus at the 3rd day after intramyocardial injection. The beneficial effects of hADSCs on MI-induced histological and cognitive changes were abolished after adding SIN-1. MI-induced ROS attacked the hippocampus to induce neurodegeneration, resulting in cognitive deficit. The remotely intramyocardial administration of hADSCs has the capacity of improved synaptic neuroplasticity in the hippocampus mediated by ROS, not the cell engraftment, after MI. KEY MESSAGES: Human adipose-derived stem cells (hADSCs) ameliorated injury after myocardial infarction by attenuating reactive oxygen species (ROS) levels. Intramyocardial administration of hADSCs remotely exerted therapeutic benefits in improving cognitive impairment after myocardial infarction. The improved synaptic neuroplasticity in the hippocampus was mediated by hADSC-inhibiting ROS, not by the stem cell engraftment.

Keywords: Cognitive function; Hippocampus; Human adipose-derived stem cells; Myocardial infarction; Passive avoidance test; Reactive oxygen species.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
hADSCs identified 3 days after infarction. A Immunofluorescent staining results of human mitochondria (green), sarcomeric α-actinin (red), and DAPI (blue). The cardiac phenotype of the transplanted hADSCs was identified from the myocardium border zone. The cardiomyocyte phenotype of transplanted hADSCs was confirmed according to the coexpression of human sarcomeric α-actinin (cardiomyocyte phenotype, red) and mitochondria (green). DAPI was used to visualize nuclei. In the merged image, the coexpression of human sarcomeric α-actinin and mitochondria showed that the antigen expression was colocalized (yellow fluorescence, arrow) (scale bar = 50 μm). B qPCR for human β-2-microglobulin was performed with sampling from myocardial border zone and hippocampus. No amplification was found in the myocardium treated with vehicle and in the hippocampus of all the groups. n = 6 each group. *P < 0.05 compared with infarcted rats treated with vehicle or ADSC/SIN-1
Fig. 2
Fig. 2
ROS analysis 3 days after infarction. A Myocardial superoxide measured by lucigenin-amplified chemiluminescence. B DHE staining from the border zone. (A) Sham, (B) vehicle, (C) ADSC, (D) ADSC/SIN-1. C Plasma superoxide levels. D Hippocampal superoxide measured by lucigenin-amplified chemiluminescence. E Hippocampal DHE staining as an index of superoxide stress and quantitative analysis. Hippocampal DHE (red fluorescent) staining showed less intense signals (nuclear position for DHE) in hADSC-treated group compared with vehicle. (A) Sham, (B) vehicle, (C) ADSC, (D) ADSC/SIN-1. F Hippocampus lipid peroxidation assessed by TBARs. The number of animals in each group is indicated in parentheses. *P < 0.05 compared with sham and infarcted rats treated with ADSC; †P < 0.05 compared with sham
Fig. 3
Fig. 3
Effects of hADSCs on the step-through latencies in rats 30 days after infarction. A Exploration time. B Retention time. Each column and bar represent mean ± SEM. The number of animals in each group is indicated in parentheses. *P < 0.05 compared with sham and infarcted rats treated with ADSC; †P < 0.05 compared with sham
Fig. 4
Fig. 4
Nissl staining and Golgi stain in rats 30 days after infarction. A Nissl staining of the cells in the dentate gyrus region showed an improvement in Nissl granules and darker staining with more ribosomes inside in the ADSC group compared to vehicle. (A) Sham, (B) vehicle, (C) ADSC, (D) ADSC/SIN-1. Scale bar = 100 μm. B Golgi stain. Representative neuron morphology with Golgi staining (scale bar = 50 μm) and the framed apical dendritic section for spine density analysis (scale bar = 5 μm). hADSC administration increases the number of dendritic apical spines in dentate gyrus. The number of animals in each group is indicated in parentheses. *P < 0.05 compared with sham and infarcted rats treated with ADSC; †P < 0.05 compared with sham
Fig. 5
Fig. 5
Synaptic plasticity in rats 30 days after infarction. A Presynaptic synaptophysin colocalizes with postsynaptic PSD95 in hippocampal dentate gyrus region. Analysis of the relative intensity of synaptophysin, PSD95, and SYN/PSD95 contacts. Quantitative data for synaptophysin and PSD95 show a significantly increased number of synaptophysin and PSD95 stained puncta in the hADSC group compared with vehicle. Importantly, the total number of synaptophysin/PSD contacts (synaptic density) was also increased in the hADSC group. B Western blot confirmation for synaptophysin and PSD95 levels in the hippocampus. Quantitative analysis of Western blot analysis. Relative abundance was obtained against that of β-actin. Results are mean ± SEM of 3 independent experiments. The number of animals in each group is indicated in parentheses. Scale bar = 50 μm. *P < 0.05 compared with sham and infarcted rats treated with ADSC; †P < 0.05 compared with sham
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