The Tale of Two Challanges: Stem Cells and Diabetic Vasculopathy

Abstract Background Diabetes is a metabolic disorder highly linked to several systemic complications. Diabetic patients largely suffer from hyperglycemia-induced macro- and micro-vascular abnormalities. Accumulating data have suggested a beneficial role of endothelial progenitor cells in diabetic microvascular diseases. Objective We evaluated the possible therapeutic effect of injecting transformed human umbilical cord mesenchymal stem cells on cardiovascular and renal functions in old diabetic rats. Methods Thirty old (18-14 months) male Wistar albino rats weighing 300-350g were used in the present study. Diabetes was induced by intra-peritoneal streptozotocin injection. Rats were assigned (10/group) to Naive (received no treatment), diabetic control (injected with saline), and diabetic transformed mesenchymal stem cell treated (TMSCs). Measurement of blood pressure and doppler studies were performed, and blood samples were collected. Animals were then scarified and large and small vessels were collected for immunohistopathology. Results Anti-CD31 immuno-staining has shown successful homing of the injected transformed stem cells to the vascular endothelium. TMSCs treated group featured reduced systolic blood pressure, heart rate and pulse wave velocity when compared to control group. TMSCs treated group had lower serum level of vascular endothelial growth factor (VEGF), interleukin1β (IL-1β) and tumor necrosis factor alpha (TNFα). Renal function parameters (KIM-1 and cystatin C)) were significantly lower in TMSCs treated group. Renal artery doppler study revealed improved blood flow and reduced resistance in the TMSCs treated group when compared to the control group. Conclusion We show here that transformed mesenchymal stem cells could be a potential therapeutic approach against hyperglycemia-induced macro- and micro-vascular complications in aged diabetics.

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Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells (huMSCs) Carrying MicroRNA-342 Relieve Protect Severe Acute Pancreatitis Injury (SAP)

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2021.2744 ◽

2021 ◽

Vol 11 (9) ◽

pp. 1838-1843

Author(s):

Xiaohong Zhou ◽

Xuzhong Hao ◽

Feifei He

Keyword(s):

Stem Cells ◽

Acute Pancreatitis ◽

Mesenchymal Stem Cells ◽

Umbilical Cord ◽

Severe Acute Pancreatitis ◽

Pancreatic Tissue ◽

Inflammatory Factors ◽

Control Group ◽

Human Umbilical Cord Blood ◽

Human Umbilical Cord

To investigate whether exosomes (exo) derived from human umbilical cord mesenchymal stem cells (huMSCs) and microRNA (miRNA)-342 have a protective effect on severe acute pancreatitis (SAP). Human umbilical cord blood was collected to extract huMSC-exo. With sham-operated mice as control group (n = 10), the other mice were induced to SAP model (n = 20), while 10 of the SAP mice received treatment with huMSC-exo. ELISA was performed to determine amylase and TAP level as well as inflammatory factors and HE staining to evaluate pathological changes of pancreatic tissue. The expression of miR-342 and Shh, Ptchl, and Smo in the Hh signal pathway was detected using RT-qPCR. The expression of miR-342 and the mRNA expression of Shh, Ptchl, and Smo was higher than that in model group (p < 0.05). The level of serum amylase, trypsinogen, and IFN-γ,Fasl, and IL-6 was upregulated in pancreas tissues of SAP mice relative to healthy mice, but their levels were decreased upon treatment with huMSC-exo and slightly higher than those of the control group, just not significantly. Collectively, the huMSC-exo may activate the Hh signaling pathway by regulating the expression of miR-342 increasing the expression of Shh, Ptchl, and Smo, and thereby healing of damaged pancreatic tissues in SAP.

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The potential role of mesenchymal stem cells in a hypoxia model induced by sodium nitrite in testes of male albino rats

Biomedical Research and Therapy ◽

10.15419/bmrat.v4i02.150 ◽

2017 ◽

Vol 4 (02) ◽

pp. 1128

Author(s):

Nadia H. Ismaeil ◽

Amany A. Osman ◽

Elham H.A. Ali ◽

Laila A. Rashed ◽

Manal A. Saleh

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Sodium Nitrite ◽

Recovery Period ◽

Male Rats ◽

Control Group ◽

Albino Rats ◽

Blood Capillaries ◽

Histopathological Alterations

Introduction: The present work aims to examine the possible role of stem cells on biochemical markers and histopathological alterations of hypoxia caused by sodium nitrite (NaNO2) toxicity in testes of male rats. Methods: In this study, 96 adult male albino rats were divided into 6 groups (16 rats each). Group 1 (G1) was the control group and received distilled H2O. Group 2 (G2) received daily NaNO2 (35 m/kg bwt/ day) via subcutaneous injection for 3 weeks. Group 3 (G3) received NaNO2 for 2 weeks and were then injected once with 2*106 mesenchymal stem cells (MSCs) intravenously and sacrificed 4 weeks later. Group 4 (G4) received NaNO2 for 2 weeks and were then injected with 2*106 MSCs followed by daily NaNO2 injection for 1 week; rats in G4 were sacrificed 4 weeks from MSCs treatment. Group 5 (G5) rats were treated with NaNO2 for 2 weeks and then left to recover for 4 weeks. Finally, Group 6 (G6) rats were treated with NaNO2 for 3 weeks and left to recover for 3 weeks, after which point they were sacrificed. Results: The results showed that NaNO2 caused oxidative damage and histopathological alterations in the rat testes, as well as increased the levels of testes malondialdehyde (MDA), nitric oxide (NO) and DNA fragmentation percentage (DNA F %). Moreover, NaNO2 decreased the elevated activities of testes catalase (CAT) and total antioxidant activity (TAA), in comparison to the control group. The histological results illustrated different distortions, vacuolization and lipid accumulations in interlobular space as well as diminution of inter cellular germ cell layers, absence of Leydig cells, irregular basement membrane of tubule, and separation within spermatogenic cells. In addition, congestion and dilation of intertubular and peripheral blood capillaries were found. Nevertheless, the administration of stem cells reduced the danger actions of sodium nitrite by enhancing biochemical marker concentration. Conclusion: There was an improvement in the histology of the rat testes, including a relatively normal order in the different stages of spermatogonia and loss of different stages of spermatocytes. Regarding the recovery period, there was also a significant improvement in each of the biochemical parameters assessed and in the histological lesions.

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Simulated Microgravity Reduces Proliferation and Reorganizes the Cytoskeleton of Human Umbilical Cord Mesenchymal Stem Cells

Physiological Research ◽

10.33549/physiolres.934472 ◽

2020 ◽

pp. 897-906

Author(s):

H CHI ◽

H SON ◽

D CHUNG ◽

L HUAN ◽

T DIEM ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Western Blot ◽

Umbilical Cord ◽

Simulated Microgravity ◽

Cellular Proliferation ◽

Cytoskeletal Proteins ◽

Control Group ◽

Human Umbilical Cord

The cytoskeleton plays a key role in cellular proliferation, cell-shape maintenance and internal cellular organization. Cells are highly sensitive to changes in microgravity, which can induce alterations in the distribution of the cytoskeletal and cell proliferation. This study aimed to assess the effects of simulated microgravity (SMG) on the proliferation and expression of major cell cycle-related regulators and cytoskeletal proteins in human umbilical cord mesenchymal stem cells (hucMSCs). A WST-1 assay showed that the proliferation of SMG-exposed hucMSCs was lower than a control group. Furthermore, flow cytometry analysis demonstrated that the percentage of SMG-exposed hucMSCs in the G0/G1 phase was higher than the control group. A western blot analysis revealed there was a downregulation of cyclin A1 and A2 expression in SMG-exposed hucMSCs as well. The expression of cyclin-dependent kinase 4 (cdk4) and 6 (cdk6) were also observed to be reduced in the SMG-exposed hucMSCs. The total nuclear intensity of SMG-exposed hucMSCs was also lower than the control group. However, there were no differences in the nuclear area or nuclear-shape value of hucMSCs from the SMG and control groups. A western blot and quantitative RT-PCR analysis showed that SMG-exposed hucMSCs experienced a downregulation of β-actin and α-tubulin compared to the control group. SMG generated the reorganization of microtubules and microfilaments in hucMSCs. Our study supports the idea that the downregulation of major cell cycle-related proteins and cytoskeletal proteins results in the remodeling of the cytoskeleton and the proliferation of hucMSCs.

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Modulation of gene transcription promoted by mesenchymal stem cells on cation-chloride cotransporter NKCC1 in experimental epilepsy

10.5327/1516-3180.684 ◽

2021 ◽

Author(s):

Giovani Zocche Junior ◽

Isadora Ghilardi ◽

Laura Provenzi ◽

Gabriel Leal ◽

Giulia Pinzetta ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Wistar Rats ◽

Brain Structures ◽

Treated Group ◽

Control Group ◽

Neural Firing ◽

Post Transplantation ◽

Neuroprotective Effects ◽

Invasive Approach

Introduction: temporal lobe epilepsy is a disorder in which synchronized and rhythmic neural firing causes spontaneous recurrent seizures (1). Refractoriness due to this condition reaches 30% of its carriers (2,3). The search for therapeutic alternatives to help cope with this disease are extremely important. Mesenchymal stem cells (MSCs) appear as a plausible treatment option, as they present a less invasive approach and due to their niche modulating character (4,5). Objectives: this study aimed to quantify the gene expression of cation-chloride cotransporter NKCC1 encoded by the SLC12A2 gene in the encephalic tissue of pilocarpine-induced epileptic rats (6,7). Design: experimental study, brain institute of Rio Grande do Sul. Methods: MSCs were obtained from the bone marrow of Wistar rats, cultured, and transplanted through intravenous injection into control and epileptic Wistar rats. The rats were divided between control group, MSCs treated group, and pilocarpine group, containing 8 individuals each (8). Expression analysis was performed using real-time polymerase chain reaction. Results: for both 1 day and 7 days post-transplantation, an increase in the NKCC1 expression in both control and epileptic treated groups as compared to its expression in untreated epileptic and control groups with special attention to the amygdala, the hippocampus and the prefrontal cortex. Conclusion: MSCs stimulated expression of NKCC1 in brain structures of rats induced by pilocarpine to epilepsy. This corroborates the hypothesis of neuroprotective effects and modulating properties of stem cells and may point to more mechanisms for investigating the functioning and collaboration of these cells as a treatment for epilepsy.

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Platelet Microparticles Accelerate Proliferation and Growth of Mesenchymal Stem Cells through Longevity-Related Genes

Archives of Iranian Medicine ◽

10.34172/aim.2021.86 ◽

2021 ◽

Vol 24 (8) ◽

pp. 607-614

Author(s):

Maryam Samareh Salavati Pour ◽

Fatemeh Hoseinpour Kasgari ◽

Alireza Farsinejad ◽

Ahmad Fatemi ◽

Gholamhossein Hassanshahi ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Real Time ◽

Real Time Pcr ◽

Treated Group ◽

Population Doubling ◽

Control Group ◽

Population Doubling Time ◽

Longevity Genes

Background: Due to their self-renewal and differentiation ability, the mesenchymal stem cells (MSCs) have been studied extensively. However, the MSCs lifespan is restricted; they undergo several divisions in vitro that cause several alternations in cellular features and relatively lessens their application. Thus, this study was aimed to assess the effect of platelet-derived microparticles (PMPs), a valuable source of proteins, microRNAs (miRNAs), and growth factors, on the expression of hTERT, c-MYC, p16, p53, and p21 as the most important aging and cell longevity genes alongside with population doubling time (PDT) of PMP-treated cells in comparison to a control group. Methods: Umbilical cord MSCs (UC-MSCs) were used in this study, whereby they reached a confluency of 30%. MSCs were treated by PMPs (50 µg/mL), and then, PDT was determined for both groups. Quantitative expression of hTERT, c-MYC, p16, p53, and p21 was examined through quantitative real-time PCR at various intervals (i.e. after five and thirty days as well as freezing-thawing process). Results: Our results demonstrated that the treated group had a shorter PDT in comparison to the control group (P<0.050). The real-Time PCR data also indicated that PMPs were able to remarkably up-regulate hTERT and c-MYC genes expression while down-regulating the expression of p16, p21, and p53 genes (P<0.050), especially following five days of treatment. Conclusion: According to these data, it appears that PMPs are a safe and effective candidate for prolonging the lifespan of UC-MSCs; however, further investigations are needed to corroborate this finding.

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Reduced-dose of Posttransplant Cyclophosphamide and Cotransplantation of Peripheral Blood Stem Cells and Human Umbilical Cord-derived Mesenchymal Stem Cells in Severe Aplastic Anemia

10.21203/rs.3.rs-31898/v1 ◽

2020 ◽

Author(s):

Yingling Zu ◽

Jian Zhou ◽

Yuewen Fu ◽

Baijun Fang ◽

Xinjian Liu ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Aplastic Anemia ◽

Peripheral Blood ◽

Control Group ◽

Human Umbilical Cord ◽

Peripheral Blood Stem Cells ◽

Reduced Dose ◽

Blood Stem Cells ◽

The Times

Abstract Background Posttransplant cyclophosphamide (PTCY) as graft-versus-host disease (GVHD) prophylaxis is an effective strategie for patients receiving matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) and haploidentical HSCT (haplo-HSCT). Methods We evaluated the effectiveness and safety of reduced-dose cyclophosphamide, 20 mg/kg for 13 patients in the MSD-HSCT group and 25 mg/kg for 22 patients in the haplo-HSCT group, on days +3 and +4 combined with cotransplantation of peripheral blood stem cells (PBSCs) and human umbilical cord-derived mesenchymal stem cells (UC-MSCs) for patients with severe aplastic anemia (SAA) retrospectively. Results In the MSD-PTCY group, the times to neutrophil and platelet engraftment were significantly shorter than those in the MSD-control group (P<0.05), 11 (range 10 to 14) days and 12 (range 9 to 15) days. The cumulative incidence of acute GVHD (aGVHD) at day +100 (15.4%) was lower in the MSD-PTCY group than in the MSD-control group(P=0.050). No patient developed chronic GVHD (cGVHD). The 1-year overall survival (OS) and event-free survival (EFS) rates in the MSD-PTCY group were 100% and 92.3%. In the haplo-PTCY group, the times to neutrophil and platelet engraftment were significantly shorter than those in the haplo-control group (P<0.05), 12 (range 9 to 15) days and 11.5 (range 9 to 17) days. The cumulative incidences of aGVHD at day +100 and 1-year cGVHD in the haplo-PTCY group were 31.8% and 18.2%. The 1-year OS and EFS rates in the haplo-PTCY group were 81.8% and 66.9%. Conclusions Reduced-dose PTCY and cotransplantation of PBSCs and UC-MSCs is feasible for patients with SAA, especially for overcoming the high incidences of aGVHD and cGVHD due to PBSCs.

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The Therapeutic Potential of Umbilical Cord Mesenchymal Stem Cells in Mice Premature Ovarian Failure

BioMed Research International ◽

10.1155/2013/690491 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 25

Author(s):

Shufang Wang ◽

Ling Yu ◽

Min Sun ◽

Sha Mu ◽

Changyong Wang ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Umbilical Cord ◽

Granulosa Cells ◽

Premature Ovarian Failure ◽

Ovarian Function ◽

Treated Group ◽

Ovarian Failure ◽

Control Group ◽

Wild Type

Mesenchymal stem cells, which are poorly immunogenic and have potent immunosuppressive activities, have emerged as promising cellular therapeutics for the treatment of several diseases. Mesenchymal-like cells derived from Wharton’s Jelly, called umbilical cord matrix stem cells (UCMSCs), reportedly secrete a variety of cytokines and growth factors, acting as trophic suppliers. Here, we used UCMSCs to treat premature ovarian failure (POF). Ovarian function was evaluated by ovulation and the number of follicles. Apoptosis of the granulosa cells (GC) was analyzed by TUNEL staining. We found that after transplantation of the UCMSCs, apoptosis of cumulus cells in the ovarian damage model was reduced and the function of the ovary had been recovered. The sex hormone level was significantly elevated in mice treated with UCMSCs. The number of follicles in the treated group was higher than in the control group. Our results demonstrate that UCMSCs can effectively restore ovary functionality and reduce apoptosis of granulosa cells. We compared the RNA expression of the UCMSCs treated group with the POF model and wild-type control group and found that the UCMSC group is most similar to the wild-type group. Our experiments provide new information regarding the treatment of ovarian function failure.

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Effect of a Decellularized Omentum Scaffold with Combination of Mesenchymal Stem Cells and Platelet-Rich Plasma on Healing of Critical-Sized Bone Defect: A Rat Model

Applied Sciences ◽

10.3390/app112210900 ◽

2021 ◽

Vol 11 (22) ◽

pp. 10900

Author(s):

Abdulsamet Emet ◽

Erdi Ozdemir ◽

Duygu Uckan Cetinkaya ◽

Emine Kilic ◽

Ramin Hashemihesar ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Platelet Rich Plasma ◽

Bone Defects ◽

Control Group ◽

Albino Rats ◽

Group 5 ◽

Group 2 ◽

Wistar Albino Rats ◽

Critical Bone Defects

The high costs and extensive time needed for the treatment of critical-sized bone defects are still major clinical concerns in orthopedic surgery; therefore, researchers continue to look for more cost and time-effective methods. This study aims to investigate the effects of a decellularized omentum scaffold with a combination of platelet-rich plasma (PRP) and mesenchymal stem cells on the healing of critical-sized bone defects. Wistar albino rats (n = 30) were investigated in five groups. Critical-sized bone defects were formed on bilateral radius shafts. No scaffold, decellularized omentum, omentum with PRP and omentum + mesenchymal stem cells was used in group 1 (control group), 2, 3 and 4, respectively. In addition, omentum with a combination of mesenchymal stem cells +PRP was used in group 5. After 6 weeks, both radiological and histological healing were evaluated comparatively among the groups. After the use of a decellularized omentum scaffold, vitality of new cells was maintained, and new bone formation occurred. When compared to the control group, radiological healing was significantly better (p = 0.047) in the omentum and omentum + PRP-treated groups. Furthermore, histological healing was better in the omentum and omentum + PRP-treated groups than the control group (p = 0.001). The use of a decellularized omentum scaffold is suitable in the healing of critical bone defects.

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Reprint-The Effect of Bone Marrow Derived Mesenchymal Stem Cells on the Survival of Random Skin Flap on Sterptozotocin-Induced Diabetic Rats

Biomedical Research and Clinical Reviews ◽

10.31579/2692-9406/007 ◽

2020 ◽

Vol 1 (4) ◽

pp. 01-08

Author(s):

Farzaneh Chehelcheraghi ◽

Khadijah Rezazadeh ◽

Khatereh Anbari

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Skin Flap ◽

Healing Process ◽

Diabetic Rats ◽

Control Group ◽

Wound Healing Process ◽

Average Weight ◽

Diabetic Patients

Background and Objective: Wound dressing and healing in diabetic patients is encountered with many problems. This study aimed to investigate the effect of bone marrow derived mesenchymal stem cells (BM-MSCs) on the survival of random skin flap (RSF) on Streptozotocin-induced diabetic rats (STZ) using an optical microscope. Materials & Methods: In this study, 60 male Albino Wistar rats were used (average weight 250-300 gr). The rats were divided into six groups: 1) Health-Non (HN), 2) Health-Cells (HC), 3) Health-Sham (HS), 4) Diabetic-Non (DN) that were became diabetic by injecting STZ 70 mg/kg intraperitoneally), 5) Diabetic-Sham (DS), and 6) Diabetic-Cell (DC). In all groups, the day of surgery was considered as the zero day, on the back area of animal, the flap was created with a size of 8 × 3 cm and the BM-MSCs were performed. The sampling was performed on day 7 after surgery from the region where Transitional Zone (TZ) necrosis was initiated. Results: BM-MSCs increased the number of blood vessels (P=0.009) and the histology parameters (wound demarcation P=0.0001, granulation tissue P=0.0001) significantly compared to the control group. But this increase was not significant in the area of the survival region. Conclusion: It was concluded that after treatment with BM-MSCs, the wound healing process in both non-diabetic and diabetic groups was increased in accordance with histological characteristics.

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Bone collagen particles combined with hUC-MSCs to repair alveolar cleft in rabbits

10.21203/rs.2.22764/v1 ◽

2020 ◽

Author(s):

Xue-Cheng Sun ◽

Hu Wang ◽

Jian-Hui Li ◽

Dan Zhang ◽

Xu Ma ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Computerized Tomography ◽

Umbilical Cord ◽

Normal Group ◽

Bone Collagen ◽

Control Group ◽

Human Umbilical Cord ◽

Micro Ct ◽

Alveolar Cleft

Abstract Background: Alveolar cleft is a kind of cleft lip and palate, which seriously affects the physical and mental health of patients. In this study, a similar model of human alveolar cleft phenotype was established in rabbits to evaluate the effect of bone collagen particles combined with human umbilical cord mesenchymal stem cells (hUC-MSCs) on the repair of alveolar cleft. Materials &Methods : In this study, 24 adult Japanese white rabbits (JWRs) were selected and randomly divided into 4 groups. Including normal group, control group, materials group and MSCs group. The model of alveolar cleft was established by removing the incisors on the left side of the upper jaw. The normal group did not receive any treatment. In the control group, the incisors were removed and sutured directly. In the material group, the incisor were removed, then filled with bone collagen particles, and finally sutured. In the MSCs group, the incisors were first removed, then filled with bone collagen granules incubated by hUC-MSCs, and then stitched. Blood biochemical analysis was performed 3 months after the operation. Skull tissues were collected for gross observation, and micro-focus computerized tomography (micro-CT) analysis. Paraffin sections were prepared for histological and immunohistochemical staining. Results: The bone collagen particles and hUC-MSCs are not biotoxic and can promote alvenlus regeneration. Bone collagen particles combined with hUC-MSCs were much better than those used alone in inducing bone repair and regeneration. Conclusions: HUC-MSCs can be used as a bone generation inducer combined with bone materials for bone regeneration and repair. Keywords: alveolar cleft，Bone collagen particle, hUC-MSCs (human umbilical cord mesenchymal stem cells),micro-focus computerized tomography (micro-CT)

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