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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 63  |  Issue : 3  |  Page : 122-127

Resveratrol enhances therapeutic effect on pancreatic regeneration in diabetes mellitus rats receiving autologous transplantation of adipose-derived stem cells


1 School of Life Science, National Taiwan Normal University, Taipei, Taiwan
2 Department of Emergency; Department of Chinese Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan
3 Department of Sports Sciences, University of Taipei, Taipei, Taiwan
4 Department of Nursing, Meiho University, Pingtung, Taiwan
5 Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
6 Department of Chinese Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan
7 Department of Pathology, Changhua Christian Hospital, Changhua; Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan
8 Institute of Research and Development, Duy Tan University, Da Nang, Vietnam
9 Department of Biotechnology, Bharathiar University, Coimbatore, Tamil Nadu, India
10 Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
11 Cardiovascular and Mitochondrial Related Diseases Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation; Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien; Department of Medical Research, China Medical University Hospital, China Medical University; Department of Biotechnology, Asia University, Taichung, Taiwan

Date of Submission10-Jan-2020
Date of Decision10-Apr-2020
Date of Acceptance21-May-2020
Date of Web Publication23-Jun-2020

Correspondence Address:
Prof. Chih-Yang Huang
Cardiovascular and Mitochondrial Related Diseases Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CJP.CJP_3_20

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  Abstract 

Pancreatic damage is the major causative agent in type 1 diabetes mellitus (DM). Several strategies have been suggested to regenerate pancreatic functions, such as stem cell transplantation and administration of active components isolating from natural herbals. This study aims to investigate if the synergistically protective effect on damaged pancreatic tissues can be observed in STZ-induced DM rats with autologous transplantation of adipose-derived stem cells (ADSC) coupling with oral administration of resveratrol. Pathological conditions can be recognized in DM rats with pancreatic damage, including reduction of islet size, suppression of survival markers, downregulation of AMPK/Sirt1 axis, and activation of apoptotic signaling. Autologous transplantation of ADSC slightly improves pancreatic functions, whereas autologous transplantation of ADSC coupling with oral administration of resveratrol significantly improves pancreatic functions in DM rats. We suggest that oral administration of resveratrol may enhance the therapeutic effect on DM patients receiving autologous transplantation of ADSC.

Keywords: Diabetes, mesenchymal stem cells, pancreas, resveratrol


How to cite this article:
Chen TS, Lai PF, Kuo CH, Day CH, Chen RJ, Ho TJ, Yeh YL, Mahalakshmi B, Padmaviswanadha V, Kuo WW, Huang CY. Resveratrol enhances therapeutic effect on pancreatic regeneration in diabetes mellitus rats receiving autologous transplantation of adipose-derived stem cells. Chin J Physiol 2020;63:122-7

How to cite this URL:
Chen TS, Lai PF, Kuo CH, Day CH, Chen RJ, Ho TJ, Yeh YL, Mahalakshmi B, Padmaviswanadha V, Kuo WW, Huang CY. Resveratrol enhances therapeutic effect on pancreatic regeneration in diabetes mellitus rats receiving autologous transplantation of adipose-derived stem cells. Chin J Physiol [serial online] 2020 [cited 2020 Aug 5];63:122-7. Available from: http://www.cjphysiology.org/text.asp?2020/63/3/122/287452

Wei-Wen Kuo & Chih-Yang Huang share equal contribution.



  Introduction Top


Type 1 diabetes mellitus (T1DM) is induced by insufficient secretion of insulin due to pancreatic damage, and loss of β-cells leads to damage of pancreatic tissue. Several cellular signalings are involved in the damage of β-cells, including suppression of survival, expression of apoptosis, increase of reactive oxygen species (ROS), and upregulation of inflammatory pathways. Mabhida et al.[1] point out that suppression of survival axis, including PI3K/Akt can be observed in β-cell damage. By contrast, upregulation of apoptotic markers can be found in damaged β-cells, such as caspase 3, tumor necrosis factor α (TNFα), and Bax.[2],[3] In addition, β-cell damage induces elevation of ROS, leading to decrease of antioxidants (superoxide dismutase and catalase) and increase of inflammatory markers (nuclear factor-kappa B [NF-κB], cyclooxygenasee 2 [COX-2], interleukin [IL]-6, and inducible nitric oxide synthase [iNOS]).[2],[3],[4]

Several strategies have been suggested to restore β-cell functions, including stem cell treatment and supplementation of active compounds isolating from natural herbals. Stem cells show potentials in repairing damaged tissue through transdifferentiation and paracrine secretion of soluble factors. Lu et al.,[5] state that hypoxia/reoxygenation induces islet damage through the upregulation of the apoptotic pathway. Coculture of damaged β-cell with mesenchymal stem cells is capable of reducing β-cell apoptosis-mediated expression of anti-apoptotic proteins, including hypoxia inducible factor (HIF)-α1 and heme oxygenase-1 (HO-1). Similarly, activation of apoptotic signaling can be observed in islet damage induced by streptozotocin (STZ) and coculture of damaged β-cell with mesenchymal stem cells can restore β-cell viability by activation of survival axis, PI3K/Akt.[6]

In addition to stem cells, resveratrol (active compound found in red wine) also shows a beneficial effect on the restoration of β-cell function. Sánchez-Lira et al.[7] reveal that elevation of apoptosis and ROS can be found in islet damage induced by STZ, and administration of resveratrol can increase β-cell viability by suppression of apoptosis signaling and ROS production. Cheng et al.[8] point out that resveratrol upregulates p-Nrf2 expression and decreases pancreatic damage in DM rats. Furthermore, resveratrol increases Sirt1 expression to restore islet function through suppression of inflammatory marker (NF-κB) and ROS production in the aging environment.[9]

From the above statement, both stem cells and resveratrol show a protective effect on pancreatic damage, but no article mentions about the synergistic effect of stem cells and resveratrol on pancreatic protection. This study aims to investigate if synergistic effect of stem cell transplantation coupling with oral administration of resveratrol can be found in pancreatic damage in DM rats induced by STZ.


  Materials and Methods Top


Chemicals and reagents

Chemicals and reagents used in this study were purchased from Sigma-Aldrich Co. LLC. (St. Louis, MO, USA). Primary antibodies for Western blotting, including Akt, p-Akt, p-Bad, Bax, Caspase 3, and Caspase 9, were purchased from Thermo Fisher Scientific Inc. (Waltham, MA, USA). Primary antibodies for western blotting, including p-IGF1R, beta-actin, AMP-activated protein kinase (AMPK), p-AMPK, and secondary antibody were purchased from Abcam PLC., (Cambridge, UK). Primary antibodies for Western blotting, including Bcl-xL, Bcl-2, Sirt1, and Cytochrome C, were purchased from Cell Signaling Technology (Danvers, MA, USA).

Isolation, culture, and characterization of adipose-derived stem cells

Mesenchymal stem cells used in this study were isolated from rat fat tissues (adipose-derived stem cells [ADSC]). Briefly, fat tissues (epididymal fat) taking from rats were minced and incubated into a digestion solution containing 0.2% (in phosphate-buffered saline) of type 2 collagenase under 37°C for 3 h. After incubation, the digestion solution was centrifuged, and the pellet was collected. The pellet then resuspended and passaged with culture medium (containing 10% fetal bovine serum, 2 mM L-glutamine, 100U/ml penicillin, and 100ug/ml streptomycin) under 37°C with 5% CO2. Stemness of cultured cells should be confirmed by positive and negative markers by flow cytometry before performing the animal study. The protocol for the animal experiment in this study was reviewed and approved by the Institute Animal Care and Use Committee of China Medical University (2017-121).

Animal model

Wistar male rats (ranging from 6 to 8 rats per group) were used in this study and purchased from BioLASCO Taiwan Co., Ltd. (Taipei, Taiwan). Male rats with 8-week-old were adapted in the animal room with a 12 h light-dark cycle, 25°C of ambient temperature, and standard chow (Lab Diet 5001, PMI Nutrition International Inc., Brentwood, MO, USA). Animals were randomly divided into four groups including Sham (n = 8), DM (diabetic rats, n = 6), DM + ADSC (diabetic rats with ADSC treatment, n = 7), and DM + R + ADSC (diabetic rats with ADSC treatment coupling with oral administration of resveratrol, n = 7). Intraperitoneal injection of STZ (50 mg/rat) was applied to the induction of diabetic rats and animals with the elevation of serum glucose level over 220 mg/dl were considered as diabetic rats. Two therapeutic strategies were used in this study, including autologous transplantation of ADSC (1 × 106 cells/rat) through intravenous injection and supplementation of resveratrol (5 mg/kg/week) via the oral route. All the experimental groups were sacrificed after observation for 2 months. The protocol for the animal study was approved by the Institute Animal Care and Use Committee of China Medical University (2017-121).

Measurement of serum insulin

Investigation of serum insulin was performed by using a commercial kit (Rat Insulin ELISA, EZRM1-13K, Sigma-Aldrich Co. LLC., St. Louis, MO, USA). Briefly, serum samples were mixed with assay buffers, then read the optical density with wavelength of 450–590 nm. The results for serum insulin were expressed as ng/ml.

Hematoxylin and eosin stain

Pancreatic tissues isolating from experimental animals were embedding to wax to investigate the histological changes. The wax-embedding tissues were minced into 0.2-μm thickness pieces then stained with hematoxylin and eosin (H & E) dyes for further observation.

Investigation of islet size

The stained slices of pancreatic tissues were placed in the microscope (Leica DM2000, Leica Microsystems, Wetzlar, Germany), and the size of the islet was measured by the scale in the microscope. Quantification of islet size was performed based on three independent measurements.

Western blotting analysis

After sacrificing, pancreatic tissues were isolated from experimental animals. Pancreatic tissues were then homogenized under liquid nitrogen. The homogenized tissues were suspended with lysis buffer and determining the concentration of tissue lysate for western blotting analysis. Briefly, tissue lysate with concentration of 40 μg was pipetted to separation gel (12% sodium dodecyl sulfate [SDS] gel) under constant voltage (75V). After separation, the SDS gels covered with polyvinylidene difluoride (PVDF) membranes were with constant voltage (50V) for protein transfer. The PVDF membranes were then washed with Tris buffered saline buffer containing 3% bovine serum albumin. After washing, membranes were covered with primary and secondary antibodies, and the proteins were visualized as blotting bands under fluorescent detector (Fujifilm LAS-3000, GE Healthcare). ImageJ software was used for quantification of the intensity of blotting bands, and the intensity of bands is proportional to protein expressions. All the quantification of blotting bands were performed by four independent results and two blotting bands were indicated as representative figure.

Statistical analysis

The experimental data were expressed as mean ± standard deviation (n ≥3), and statistical analysis was performed by ANOVA. The significance between groups was considered at the P < 0.05 level.


  Results Top


Serum glucose and insulin levels

STZ treatment damages pancreatic tissues in experimental animals, leading to increase serum level of glucose. As shown in [Figure 1]a, we can find that the levels of serum glucose for Sham, DM, DM+ADSC and DM+R+ADSC follows the order of 121 ± 15, 463 ± 89, 362 ± 56, and 250 ± 36 mg/dl. Further, level of serum glucose in DM group is significantly higher than Sham (DM > Sham, P < 0.01) and DM+R+ADSC (DM > DM+R+ADSC, P < 0.05). [Figure 1]b shows serum insulin levels for experimental animals. We can find that the levels of serum insulin for Sham, DM, DM+ADSC, and DM+R+ADSC follows the order of 5.5 ± 0.9, 2.1 ± 0.4, 2.6 ± 0.3 and 3.5 ± 0.8 ng/ml. Further, the level of serum insulin in the DM group is significantly lower than Sham (DM < Sham, P < 0.05), and DM+R+ADSC group shows significantly higher in serum insulin than DM group (DM < DM+R+ADSC, P < 0.01).
Figure 1: Serum glucose and insulin levels. (a) Investigation of blood glucose levels for experimental animals and (b) investigation of serum insulin levels for experimental animals. Sham (n = 8), control group; DM (n = 6), diabetes group; DM+ADSC (n = 7), DM group with transplantation of adipose-derived stem cell; DM+R+ADSC (n = 7), DM+ADSC group with oral administration of resveratrol.*Compared to Sham, P < 0.05;**Compared to Sham, P < 0.01;#Compared to DM, P < 0.05. DM: Diabetes mellitus, ADSC: Adipose-derived stem cells.

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Histological observation

Histological changes for pancreatic tissues can be observed by H & E stain. In [Figure 2]a, islet diameters for Sham, DM, DM+ADSC and DM+R+ADSC groups are 19 ± 1 μm, 14 ± 1, 15 ± 1, and 16 ± 1 μm, respectively. [Figure 2]b shows the quantification of islet diameters for experimental animals. We can find that the islet diameter for the Sham group is significantly larger than the DM group (Sham > DM, P < 0.05). Similar, DM+R+ADSC group is significantly larger than DM group (DM+R+ADSC > DM, P < 0.05).
Figure 2: Investigation of islet diameter for experimental animals. (a) H & E stain, (b) quantification. Sham (n = 8), control group; DM (n = 6), diabetes group; DM+ADSC (n = 7), DM group with transplantation of adipose-derived stem cell; DM+R+ADSC (n = 7), DM+ADSC group with oral administration of resveratrol.*Compared to Sham group, P < 0.05;#Compared to DM group, P < 0.05. DM: Diabetes mellitus, ADSC: Adipose-derived stem cells, H&E stain: Hematoxylin and eosin stain.

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Protein expression for experimental animals

Investigation of protein expression can be achieved by using western blotting analysis. In [Figure 3]a, compared to the Sham group, suppression of survival proteins can be observed in the DM group, including p-IGFR, Akt, p-Akt, Bcl-xL, Bcl-2, and p-Bad. By contrast, significant upregulation of survival proteins can be found in DM+R+ADSC group when compared to the DM group. [Figure 3]b and [Figure 3]c show the quantification for expression of survival proteins in experimental animals, including p-Akt/Akt ratio and Bcl-xL/β-actin ratio. [Figure 4] shows the expression of Sirt1 signalings. In [Figure 4]a, we can observe that diabetes downregulates p-AMPK, AMPK and Sirt1 in pancreatic tissues (DM group), whereas significantly upregulation of p-AMPK, AMPK and Sirt1 can be found in both of DM+ADSC and DM+R+ADSC groups when compared to DM group. [Figure 4]b and [Figure 4]c illustrate the quantification of p-AMPK/AMPK ratio and Sirt1/β-actin ratio. [Figure 5] explores the expression of apoptotic markers for pancreatic tissues in experimental animals. In [Figure 5]a, the upregulation of apoptotic proteins can be found in the DM group, such as Bax, cytochrome C, Caspase 9, and Caspase 3 when compared to the Sham group. By contrast, apoptotic proteins are suppressed in both of DM+ADSC and DM+R+ADSC groups when compared to the DM group. [Figure 5]b shows the quantification of the cleaved-caspase 3/β-actin ratio.
Figure 3: Western blotting analysis of protein expression in pancreatic tissues. (a) Survival proteins, (b) quantification of p-Akt/Akt ratio, and (c) quantification of Bcl-xL/β-actin ratio. Sham (n = 8), control group; DM (n = 6), diabetes group; DM+ADSC (n = 7), DM group with transplantation of adipose-derived stem cell; DM+R+ADSC (n = 7), DM + ADSC group with oral administration of resveratrol.*Compared to Sham, P < 0.05;#Compared to DM, P < 0.05;##Comparted to DM, P < 0.01. DM: Diabetes mellitus, ADSC: Adipose-derived stem cells.

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Figure 4: Western blotting analysis of protein expression in pancreatic tissues. (a) Sirt1 signalings, (b) quantification of p-AMPK/AMPK ratio, and (c) quantification of Sirt1/β-actin ratio. Sham (n = 8), control group; DM (n = 6), diabetes group; DM +ADSC (n = 7), DM group with transplantation of adipose-derived stem cell; DM+R+ADSC (n = 7), DM+ADSC group with oral administration of resveratrol.*Compared to Sham, P < 0.05;**Compared to Sham, P < 0.01;#Compared to DM, P < 0.05;###Comparted to DM, P < 0.001. DM: Diabetes mellitus, ADSC: Adipose-derived stem cells.

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Figure 5: Western blotting analysis of protein expression in pancreatic tissues. (a) Apoptotic proteins, and (b) quantification of cleaved-caspase 3. Sham (n = 8), control group; DM (n = 6), diabetes group; DM+ADSC (n = 7), DM group with transplantation of adipose-derived stem cell; DM+R+ADSC (n = 7), DM+ADSC group with oral administration of resveratrol.**Compared to Sham, P < 0.01;##Compared to DM, P < 0.01. DM: Diabetes mellitus, ADSC: Adipose-derived stem cells.

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  Discussion Top


From the above statements, we can summarize the experimental findings as follows. (I) In DM rats, some pathological conditions can be recognized in damaged pancreatic tissues, including elevation of blood glucose level, reduction of islet size, suppression of survival markers, downregulation of AMPK/Sirt1 axis, and activation of apoptotic signaling. (II) Autologous transplantation of ADSC in DM rats shows a protective effect on damaged pancreatic tissues. (III) Autologous transplantation of ADSC coupling with oral administration of resveratrol significantly improves pathological conditions aforementioned in damaged pancreatic tissues in DM rats.

The only variable between the two groups DM+ADSC and DM+R+ADSC is the oral administration of resveratrol (R). This means that oral administration of resveratrol increases the expression of p-Akt [Figure 3]a and Sirt1 [Figure 4]a in DM+R+ADSC than DM+ADSC (without oral administration). Li et al.[10] point out that resveratrol inhibits neuropathic pain by activation of Sirt1 and Akt expression. Wang et al.[11] state that resveratrol protects lung injury by upregulation of Sirt1/p-Akt pathway. Thus previous studies indicate that resveratrol shows a protective effect on cell damage by activation of Sirt1 and Akt. In this study, we can find that oral administration of resveratrol increases Sirt1 and p-Akt expression in DM+R+ADSC, but not in DM+ADSC group. The findings are consistent with previous studies. From the above statement, we find that oral resveratrol shows a beneficial effect on pancreatic damage through the expression of Sirt1 and p-Akt. This does not mean that the transplantation of ADSC shows no protective effect on pancreatic damage. In [Figure 5]a, we can find that both of DM+ADSC and DM+R+ADSC can inhibit the apoptotic pathway through suppression of cleaved caspase 3. Therefore, we can speculate that oral administration of resveratrol coupling transplantation of ADSC shows a protective effect on pancreatic damage through the expression of Sirt1/p-Akt and suppression of caspase 3. By contrast, transplantation of ADSC shows a protective effect on pancreatic damage through suppression of caspase 3.

Paracrine secretion of soluble factors is one of the characteristics of stem cells for repairing damaged tissue. Brandhorst et al.[12] mentioned that islet damage induced by hypoxia can be restored by culturing with mesenchymal stem cell-conditioned medium. This means that factors releasing from stem cells to culture medium play important roles in repairing damaged islet. Furthermore, paracrine secretion of hepatocyte growth factor (HGF) from stem cells blocks the inflammatory response of β-cells through downregulation of pro-inflammatory markers, including IL-1β, TNFα, and interferon-γ.[13] This should be one of the reasons why the autologous transplantation of ADSC slightly improves pancreatic functions in DM rats in this study.

From the above statements, compared to autologous transplantation of ADSC alone, we find that autologous transplantation of ADSC coupling with oral administration of resveratrol significantly improves pancreatic functions in DM rats. This implies that resveratrol plays an important role in the restoration of pancreatic functions in DM rats receiving ADSC transplantation. Lei et al.[14] state that aged stem cells culturing with resveratrol can significantly increase the paracrine effect of soluble factors. Similarly, Zhang et al.[15] suggests that resveratrol improves human umbilical-derived mesenchymal stem cells repair for cisplatin-induced acute kidney injury via increasing secretion of platelet-derived growth factor DD (PDGF-DD). These studies point out that resveratrol can increase stem cell function through elevation of paracrine secretion of soluble factors.


  Conclusion Top


In conclusion, we speculate that resveratrol may play dual roles in the restoration of pancreatic functions in DM rats receiving autologous transplantation of ADSC including (I) resveratrol directly shows protective effect on damaged pancreatic tissue as previous mentioned; (II) resveratrol may increase paracrine secretion of soluble factors from ADSC and therefore significantly improves stem cell function in pancreatic regeneration. The experimental results are expressed in [Figure 6]. The findings of this study provide a beneficial strategy for clinical uses implying that oral administration of resveratrol may enhance the therapeutic effect on pancreatic regeneration in DM patients with autologous transplantation of ADSC.
Figure 6: Graphic summary of this study.

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Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]



 

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