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. 2023 Dec 18:2023:3784843.
doi: 10.1155/2023/3784843. eCollection 2023.

Combination Therapy with Platelet-Rich Plasma and Epidermal Neural Crest Stem Cells Increases Treatment Efficacy in Vascular Dementia

Somayeh Akbari  1   2 , Masoud Haghani  1   2 , Mojtaba Ghobadi  2 , Etrat Hooshmandi  3 , Afshin Borhani Haghighi  3 , Mohammad Saied Salehi  3 , Sareh Pandamooz  4 , Negar Azarpira  5 , Afsoon Afshari  6 , Shahrbanoo Zabihi  2 , Marzieh Nemati  2 , Mahnaz Bayat  3
Affiliations

Combination Therapy with Platelet-Rich Plasma and Epidermal Neural Crest Stem Cells Increases Treatment Efficacy in Vascular Dementia

Somayeh Akbari et al. Stem Cells Int. .

Abstract

This study aimed to evaluate the efficacy and treatment mechanism of platelet-rich plasma (PRP) and neural crest-derived epidermal stem cells (ESCs) in their administration alone and combination in vascular dementia (VaD) model by two-vessel occlusion (2VO). Methods. Sixty-six rats were divided into six groups: the control, sham, 2VO + vehicle, 2VO + PRP, 2VO + ESC, and 2VO + ESC + PRP. The treated groups received 1 million cells on days 4, 14, and 21 with or without 500 µl PRP (twice a week) after 2VO. The memory performance and anxiety were evaluated by behavioral tests including open field, passive avoidance, and Morris water maze. The basal-synaptic transmission (BST) and long-term potentiation (LTP) were assessed through field-potential recordings of the CA1. The mRNA expression levels of IGF-1, TGF-β1, PSD-95, and GSk-3β were measured in the rat hippocampus by quantitative reverse transcription polymerase chain reaction. Results. The results demonstrated impaired learning, memory, and synaptic plasticity in the 2VO rats, along with a significant decrease in the expression of IGF-1, TGF-β1, PSD-95, and upregulation of GSK-3β. Treatment with ESC alone and ESC + PRP showed similar improvements in spatial memory and LTP induction, with associated upregulation of PSD-95 and downregulation of GSK-3β. However, only the ESC + PRP group showed recovery in BST. Furthermore, combination therapy was more effective than PRP monotherapy for LTP and memory. Conclusions. The transplantation of ESC showed better effects than PRP alone, and combination therapy increased the treatment efficacy with the recovery of BST. This finding may be a clue for the combination therapy of ESC and PRP for VaD.

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Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
The schematic representation of different methods such as 2VO surgery, behavioral tests, and timeline in transplantation of the epidermal stem cells (ESC) and platelet-rich plasma (PRP) injection in two-vessel occlusion (2VO) rats.
Figure 2
Figure 2
The rat whiskers pad (a). The isolated individual hair follicles (b). Seven days after explanation, the stem cells began to migrate from the hair follicle (c). Immunostaining was performed against nestin and Sox10 as neural crest stem cell markers. The actin markers with Alexa Fluor 488 conjugated secondary antibodies emitted green fluorescence, scale bar = 50 μm (d, e) The viability of stem cells was also assessed by fluorescein diacetate (FDA) staining, scale bar = 100 μm (f). The cell nuclei were counterstained blue with 4ʹ,6-diamidino-2-phenylindole (DAPI).
Figure 3
Figure 3
The evaluation of anxiety-like behaviors in the studied groups by open-field tasks. Transplantation of epidermal stem cells (ESC) in 2VO + ESC and combined treatment in 2VO + ESC + PRP groups showed a significant decrease in the peripheral time and an increase in the central time relative to the values in the 2VO + V group (a, b). In PRP, ESC, and combined groups, the grooming number significantly decreased compared to the 2VO + V group (c). The values are shown as mean ± SEM. Significant differences with respect to the sham ( ∗∗P < 0.01,  ∗∗∗P < 0.001) and 2VO + V ( ##P < 0.01, ###P < 0.001). Control (n = 9), sham (n = 9), 2VO + V (n = 10), 2VO + PRP (n = 9), 2VO + ESC (n = 11), and 2VO + ESC + PRP (n = 10). One-way ANOVA with the post hoc test.
Figure 4
Figure 4
The evaluation of fear memory in the studied groups by passive avoidance task. Significantly higher STL times relative to the 2VO + V group were found in the 2VO + ESC, 2VO + PRP and in the 2VO + ESC + PRP groups (a). The number of shocks was at the same level in all groups (b). The values are shown as mean ± SEM. Significant differences with respect to the sham ( ∗∗P < 0.01) and 2VO + V (##P < 0.01, ###P < 0.001). Control (n = 9), sham (n = 9), 2VO + V (n = 10), 2VO + PRP (n = 9), 2VO + ESC (n = 11), and 2VO + ESC + PRP (n = 10). One-way ANOVA with the post hoc test.
Figure 5
Figure 5
The evaluation of spatial learning and memory by Morris water maze in all groups. The PRP injection in the 2VO + PRP group led to a significant decline in the escape latency time in the third block compared to the 2VO + V group. The escape latency time during the three blocks in the 2VO + ESC and 2VO + ESC + PRP groups significantly decreased compared to the 2VO + V group (two-way ANOVA) (a). In the probe trial, better memory retention was recorded in the 2VO + ESC and 2VO + ESC + PRP groups relative to the 2VO + V group (b). (One-way ANOVA with post hoc test). Swimming speed was the same in all the studied groups (c). Significant differences with respect to the sham ( ∗P < 0.05,  ∗∗P < 0.01, and  ∗∗∗P < 0.001) and 2VO + V (#P < 0.05, ##P < 0.01, ###P < 0.001). Significant differences between 2VO + ESC + PRP group respect to the 2VO + PRP group ($$P < 0.01). The values are shown as mean ± SEM. Control (n = 9), sham (n = 9), 2VO + V (n = 10), 2VO + PRP (n = 9), 2VO + ESC (n = 11), and 2VO + ESC + PRP (n = 10).
Figure 6
Figure 6
The basal synaptic transmission (BST) of the hippocampal CA1 neurons was assessed by input/output curve in all groups. The input/output curve (a). A significant right and downward shift in the input/output curve of 2VO rats shows BST decline following the 2VO model. A significant decrease in the half-maximal fEPSP amplitude in the 2VO + V group relative to the sham group (b). The combination therapy of PRP and cells showed better effects and a significant increase in the half-maximum response compared to 2VO + V group. Significant differences were relative to the sham ( ∗P < 0.05) and 2VO + V (#P < 0.05). Control (n = 8), sham (n = 7), 2VO + V (n = 8), 2VO + PRP (n = 8), 2VO + ESC (n = 8), and 2VO + ESC + PRP (n = 7). One-way ANOVA with the post hoc test.
Figure 7
Figure 7
The evaluation of short-term synaptic plasticity in studied groups by paired-puls ratio (PPR) calculation. For different ISIs (25−250 ms). The sample traces of responses (a), the PPR was plotted by linear graph before (b), and after (c) HFS delivery. There was no significant difference between all the studied groups before or after HFS in the PPR. The values are shown as mean ± SEM. Control (n = 8), sham (n = 7), 2VO + V (n = 8), 2VO + PRP (n = 8), 2VO + ESC (n = 8), and 2VO + ESC + PRP (n = 7).
Figure 8
Figure 8
The comparison of long-term potentiation (LTP) induction between different studied groups. LTP induction in sample traces of responses (a). After high-frequency stimulation (HFS), the percentage of the change of the fEPSP amplitude compared to the baseline was compared between all groups (b). The means of fEPSP amplitude after HFS were compared between all groups (c). Significant differences with respect to the sham ( ∗P < 0.05,  ∗∗P < 0.01) and 2VO + V (#P < 0.05, ##P < 0.01). The values are shown as mean ± SEM. Control (n = 8), sham (n = 7), 2VO + V (n = 8), 2VO + PRP (n = 8), 2VO + ESC (n = 8), and 2VO + ESC + PRP (n = 7).
Figure 9
Figure 9
mRNA expression levels of IGF1, TGF-β1, PSD-95, and GSk-3β in the rat hippocampus (a–d). The values are shown as mean ± SEM. Significant differences with respect to the sham ( ∗P < 0.05,  ∗∗P < 0.01) and 2VO + V (#P < 0.05, ##P < 0.01). The values are shown as mean ± SEM. Control (n = 6), sham (n = 6), 2VO + V (n = 5), 2VO + PRP (n = 5), 2VO + ESC (n = 5), and 2VO + ESC + PRP (n = 5).
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