Adjunctive mesenchymal stem/stromal cells augment microvascular function in poststenotic kidneys treated with low-energy shockwave therapy.
Ontology highlight
ABSTRACT:
SUBMITTER: Chen XJ
PROVIDER: S-EPMC7529809 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Microvascular rarefaction distal to renal artery stenosis is linked to renal dysfunction and poor outcomes. Low-energy shockwave therapy stimulates angiogenesis, but the effect on the kidney microvasculature is unknown. We hypothesized that low-energy shockwave therapy would restore the microcirculation and alleviate renal dysfunction in renovascular disease. Normal pigs and pigs subjected to 3 weeks of renal artery stenosis were treated with six sessions of low-energy shockwave (biweekly for 3 consecutive weeks) or left untreated. We assessed BP, urinary protein, stenotic renal blood flow, GFR, microvascular structure, and oxygenation in vivo 4 weeks after completion of treatment, and then, we assessed expression of angiogenic factors and mechanotransducers (focal adhesion kinase and ?1-integrin) ex vivo A 3-week low-energy shockwave regimen attenuated renovascular hypertension, normalized stenotic kidney microvascular density and oxygenation, stabilized function, and alleviated fibrosis in pigs subjected to renal artery stenosis. These effects associated with elevated renal expression of angiogenic factors and mechanotransducers, particularly in proximal tubular cells. In additional pigs with prolonged (6 weeks) renal artery stenosis, shockwave therapy also decreased BP and improved GFR, microvascular density, and oxygenation in the stenotic kidney. This shockwave regimen did not cause detectable kidney injury in normal pigs. In conclusion, low-energy shockwave therapy improves stenotic kidney function, likely in part by mechanotransduction-mediated expression of angiogenic factors in proximal tubular cells, and it may ameliorate renovascular hypertension. Low-energy shockwave therapy may serve as a novel noninvasive intervention in the management of renovascular disease.
| S-EPMC5118474 | biostudies-literature
Project description:Background aimsOne important problem commonly encountered after hepatocyte transplantation is the low numbers of transplanted cells found in the graft. If hepatocyte transplantation is to be a viable therapeutic approach, significant liver parenchyma repopulation is required. Mesenchymal stromal cells (MSC) produce high levels of various growth factors, cytokines and metalloproteinases, and have immunomodulatory effects. We therefore hypothesized that co-transplantation of MSC with human fetal hepatocytes (hFH) could augment in vivo expansion after transplantation. We investigated the ability of human fetal liver MSC (hFLMSC) to augment expansion of phenotypically and functionally well-characterized hFH.MethodsTwo million hFH (passage 6) were either transplanted alone or together (1:1 ratio) with green fluorescence protein-expressing hFLMSC into the spleen of C57BL/6 nude mice with retrorsine-induced liver injury.ResultsAfter 4 weeks, engraftment of cells was detected by fluorescence in situ hybridization using a human-specific DNA probe. Significantly higher numbers of cells expressing human cytokeratin (CK)8, CK18, CK19, Cysteine-rich MNNG HOS Transforming gene (c-Met), alpha-fetoprotein (AFP), human nuclear antigen, mitochondrial antigen, hepatocyte-specific antigen and albumin (ALB) were present in the livers of recipient animals co-transplanted with hFLMSC compared with those without. Furthermore, expression of human hepatocyte nuclear factor (HNF)-4α and HNF-1β, and cytochrome P450 (CYP) 3A7 mRNA was demonstrated by reverse transcriptase-polymerase chain reaction (RT-PCR) in these animals. In addition, significantly increased amounts of human ALB were detected. Importantly, hFLMSC did not transdifferentiate into hepatocytes.ConclusionsOur study reports the use of a novel strategy for enhanced liver repopulation and thereby advances this experimental procedure closer to clinical liver cell therapy.
| S-EPMC3411318 | biostudies-literature
Project description:Mesenchymal stromal cells (MSC) are potential renal therapeutics. Clinically, results are mixed partly because MSC tropism to kidneys is minimal following infusion. Ultrasound augmentation of the renal microenvironment is becoming increasingly-important in renal MSC therapies. We demonstrated pulsed-focused-ultrasound (pFUS) increases enhanced homing permeability and retention of MSC in mouse kidneys. Here, we characterized the temporal proteomic response to pFUS in mouse kidneys and its association with MSC tropism. pFUS induced molecular cascades of initial increases in tumor necrosis factor-? (TNF?) and interleukin (IL)-1?, that activated nuclear factor kappa-light-chain-enhancer of activated B cells (NF?B) and cyclooxygenase-2 (COX2) pathways without cell death. This was followed by a 24-48 hour-long response of increased cell adhesion molecules (CAM), trophic and anti-inflammatory factors. Pretreating animals with anti-inflammatory drugs etanercept (TNF? inhibitor), anakinra (IL-1 receptor antagonist), prednisone (NF?B translocation inhibitor), or ibuprofen (COX inhibitor) suppressed molecular changes and inhibited renal MSC tropism. We further examined the role of COX2 using a COX2-knock-out mouse where pFUS was unable to increase MSC tropism. These results demonstrate that renal micro-environmental changes induce MSC tropism and could influence the therapeutic efficacy of MSC. Optimizing the microenvironment and understanding drug effects will enable improvements in MSC therapies for renal disease.
| S-EPMC5561076 | biostudies-literature
Project description:Renal fibrosis is one of the largest global health care problems, and microvascular (MV) injury is important in the development of progressive fibrosis. Although conventional cell therapy suppresses kidney injury via the role of vasoprotective cytokines, the effects are limited due to low retention of administered cells. We recently described that transplantation of hepatocyte growth factor (HGF)-transgenic mesothelial cell sheets showed a remarkable cell survival and strong therapeutic effects in a rat renal fibrosis model. Due to the translational hurdles of transgenic cells, we here applied this technique for allogeneic transplantation using rat bone marrow mesenchymal stromal cells (MSCs). MSC sheets were transplanted onto the kidney surface of a rat renal ischemia-reperfusion-injury model and the effects were compared between those in untreated rats and those receiving intravenous (IV) administration of the cells. We found that donor-cell survival was superior in the cell sheet group relative to the IV group, and that the cell sheets secreted HGF and vascular endothelial growth factor (VEGF) up to day 14. Transplantation of cell sheets increased the expression of activated HGF/VEGF receptors in the kidney. There was no evidence of migration of transplanted cells into the kidney parenchyma. Additionally, the cell sheets significantly suppressed renal dysfunction, MV injury, and fibrosis as compared with that observed in the untreated and IV groups. Furthermore, we demonstrated that the MSC sheet protected MV density in the whole kidney according to three-dimensional microcomputed tomography. In conclusion, MSC sheets strongly prevented renal fibrosis via MV protection, suggesting that this strategy represents a potential novel therapy for various kidney diseases. Stem Cells Translational Medicine 2019;8:1330&1341.
| S-EPMC6877761 | biostudies-literature
Project description:As result of the current demographic changes, osteoporosis and osteoporotic fractures are becoming an increasing social and economic burden. In this experimental study, extracorporeal shock wave therapy (ESWT), was evaluated as a treatment option for the improvement of osteoporotic fracture healing.A well-established fracture model in the metaphyseal tibia in the osteoporotic rat was used. 132 animals were divided into 11 groups, with 12 animals each, consisting of one sham-operated group and 10 ovariectomized (osteoporotic) groups, of which 9 received ESWT treatment. Different energy flux intensities (0.15 mJ/mm2, 0.35 mJ/mm2, or 0.55 mJ/mm2) as well as different numbers of ESWT applications (once, three times, or five times throughout the 35-day healing period) were applied to the osteoporotic fractures. Fracture healing was investigated quantitatively and qualitatively using micro-CT imaging, quantitative real-time polymerase chain reaction (qRT-PCR) analysis, histomorphometric analysis and biomechanical analysis.The results of this study show a qualitative and quantitative improvement in the osteoporotic fracture healing under low-energy (energy flux intensity: 0,15 mJ/mm2) ESWT and with fewer treatment applications per healing period.In conclusion, low-energy ESWT seems to exhibit a beneficial effect on the healing of osteoporotic fractures, leading to improved biomechanical properties, enhanced callus-quantity and -quality, and an increase in the expression of bone specific transcription factors. The results suggest that low-energy ESWT, as main treatment or as adjunctive treatment in addition to a surgical intervention, may prove to be an effective, simple to use, and cost-efficient option for the qualitative and quantitative improvement of osteoporotic fracture healing.
| S-EPMC5726728 | biostudies-literature
Project description:BACKGROUND:Mesenchymal stromal cell (MSC) stemness capacity diminishes over prolonged in vitro culture, which negatively affects their application in regenerative medicine. To slow down the senescence of MSCs, here, we have evaluated the in vitro effects of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMPK activator, and nicotinamide (NAM), an activator of sirtuin1 (SIRT1). METHODS:Human adipose-derived MSCs were cultured to passage (P) 5. Subsequently, the cells were grown in either normal medium alone (control group), the medium supplemented with AICAR (1?mM) and NAM (5?mM), or in the presence of both for 5 weeks to P10. Cell proliferation, differentiation capacity, level of apoptosis and autophagy, morphological changes, total cellular reactive oxygen species (ROS), and activity of mTORC1 and AMPK were compared among different treatment groups. RESULTS:MSCs treated with AICAR, NAM, or both displayed an increase in proliferation and osteogenic differentiation, which was augmented in the group receiving both. Treatment with AICAR or NAM led to decreased expression of ?-galactosidase, reduced accumulation of dysfunctional lysosomes, and characteristic morphologic features of young MSCs. Furthermore, while NAM administration could significantly reduce the total cellular ROS in aged MSCs, AICAR treatment did not. Moreover, AICAR-treated cells possess a high proliferation capacity; however, they also show the highest level of cellular apoptosis. The observed effects of AICAR and NAM were in light of the attenuated mTORC1 activity and increased AMPK activity and autophagy. CONCLUSIONS:Selective inhibition of mTORC1 by AICAR and NAM boosts autophagy, retains MSCs' self-renewal and multi-lineage differentiation capacity, and postpones senescence-associated changes after prolonged in vitro culture. Additionally, co-administration of AICAR and NAM shows an additive or probably a synergistic effect on cellular senescence.
| S-EPMC6998366 | biostudies-literature
Project description:BackgroundPrevious outcome studies for extracorporeal shock wave therapy (ESWT) have included clinically diagnosed greater trochanteric pain syndrome (GTPS). The purpose of this study is to investigate outcome of ESWT on GTPS with gluteal tendinopathy documented by magnetic resonance imaging (MRI).MethodsMedical records of 38 consecutive patients were retrospectively reviewed, who underwent ESWT for GTPS with MRI-documented gluteal tendinopathy (> 6 months). ESWT was conducted (1/week) when the Roles-Maudsley score (RMS) showed "Poor" or "Fair" grade after conservative treatment until RMS had reached "Good" or "Excellent" grade (treatment success) or until 12 treatments had been applied. Numeric rating scale (NRS) and RMS were evaluated before, 1 week after (immediate follow-up) and mean 27 months after ESWT program (long-term follow-up). Success rate was calculated at each follow-up point.ResultsInitial NRS (5.9 ± 1.6) significantly decreased at immediate (2.5 ± 1.5, p< 0.01) and long-term follow-up (3.3 ± 3.0, p< 0.01), respectively. Success rates were 83.3% (immediate) and 55.6% (long-term), respectively. There was no correlation among age, symptom duration and NRS.ConclusionLow-energy ESWT can be an effective treatment for pain relief in chronic GTPS with MRI-documented gluteal tendinopathy. However, its long-term effect appears to decrease with time.
| S-EPMC6050036 | biostudies-literature
Project description:Introduction. Low-energy shockwave therapy (LESWT) has been shown to improve erectile function in patients suffering from diabetes mellitus (DM)-associated erectile dysfunction (ED). However, the underlying mechanism remains unknown. Aim. The aim of this study is to investigate whether LESWT can ameliorate DM-associated ED in a rat model and examine the associated changes in the erectile tissues. Methods. Newborn male rats were intraperitoneally injected with 5-ethynyl-2-deoxyuridine (EdU; 50 mg/kg) for the purpose of tracking endogenous mesenchymal stem cells (MSCs). Eight weeks later, eight of these rats were randomly chosen to serve as normal control (N group). The remaining rats were injected intraperitoneally with 60 mg/kg of streptozotocin (STZ) to induce DM. Eight of these rats were randomly chosen to serve as DM control (DM group), whereas another eight rats were subject to shockwave (SW) treatment (DM+SW group). Each rat in the DM+SW group received 300 shocks at energy level of 0.1 mJ/mm(2) and frequency of 120/minute. This procedure was repeated three times a week for 2 weeks. Another 2 weeks later, all 24 rats were evaluated for erectile function by intracavernous pressure (ICP) measurement. Afterward, their penile tissues were examined by histology. Main Outcome Measures. Erectile function was measured by ICP. Neuronal nitric oxide synthase (nNOS)-positive nerves and the endothelium were examined by immunofluorescence staining. Smooth muscle and MSCs were examined by phalloidin and EdU staining, respectively. Results. STZ treatment caused a significant decrease in erectile function and in the number of nNOS-positive nerves and in endothelial and smooth muscle contents. These DM-associated deficits were all partially but significantly reversed by LESWT. MSCs (EdU-positive cells) were significantly more numerous in DM+SW than in DM rats. Conclusion. LESWT can partially ameliorate DM-associated ED by promoting regeneration of nNOS-positive nerves, endothelium, and smooth muscle in the penis. These beneficial effects appear to be mediated by recruitment of endogenous MSCs. Qiu X, Lin G, Xin Z, Ferretti L, Zhang H, Lue TF, and Lin C-S. Effects of low-energy shockwave therapy on the erectile function and tissue of a diabetic rat model. J Sex Med 2013;10:738-746.
| S-EPMC3593747 | biostudies-literature
Project description:The blood-cerebrospinal fluid barrier (BCSFB) is another gatekeeper between systemic circulation and the central nervous system (CNS), mainly present at the boundary between choroid plexuses and the ventricular system. This study demonstrates BCSFB opening in rats by single pulse of low-energy focused shockwave (FSW, energy flux density 0.03 mJ/mm2, 2 × 106 microbubbles/kg) treatment at lateral ventricle, resulting in significantly elevated cerebrospinal fluid (CSF) concentrations of systemically-administered gastrodin (GTD) (4 times vs. control within 3 hrs) that remained detectable for 24 hrs. The FSW-GTD group had significantly lower Racine's scale (<4) and zero mortality (n = 30) after lithium-pilocarpine-induced epilepsy. Electrophysiological recordings showed decreased epileptiform discharges, and brain section histology revealed reduced inflammation, oxidative stress and apoptosis, when compared with groups without FSW (Racine's scale: 4 ∼ 5; mortality: 26.67 ∼ 36.67%). FSW-mediated BCSFB opening provides a promising alternative for controlled-delivery of therapeutics into the CNS, offering rapid and widespread medication distribution. The technique could by applied in the development of novel therapies for various CNS diseases.
| S-EPMC8408522 | biostudies-literature
Project description:A primary component of exercise, mechanical signals, when applied in the form of low intensity vibration (LIV), increases mesenchymal stem cell (MSC) osteogenesis and proliferation. While it is generally accepted that exercise effectively combats the deleterious effects of aging in the musculoskeletal system, how long-term exercise affects stem cell aging, which is typified by reduced proliferative and differentiative capacity, is not well explored. As a first step in understanding the effect of long-term application of mechanical signals on stem cell function, we investigated the effect of LIV during in vitro expansion of MSCs. Primary MSCs were subjected to either a control or to a twice-daily LIV regimen for up to sixty cell passages (P60) under in vitro cell expansion conditions. LIV effects were assessed at both early passage (EP) and late passage (LP). At the end of the experiment, P60 cultures exposed to LIV maintained a 28% increase of cell doubling and a 39% reduction in senescence-associated ?-galactosidase activity (p?<?0.01) but no changes in telomere lengths and p16INK4a levels were observed. Prolonged culture-associated decreases in osteogenic and adipogenic capacity were partially protected by LIV in both EP and LP groups (p?<?0.05). Mass spectroscopy of late passage MSC indicated a synergistic decrease of actin and microtubule cytoskeleton-associated proteins in both control and LIV groups while LIV induced a recovery of proteins associated with oxidative reductase activity. In summary, our findings show that the application of long-term mechanical challenge (+LIV) during in vitro expansion of MSCs for sixty passages significantly alters MSC proliferation, differentiation and structure. This suggests LIV as a potential tool to investigate the role of physical activity during aging.
| S-EPMC7286897 | biostudies-literature