The potency of mesenchymal stem/stromal cells: does donor sex matter?

Mesenchymal stem/stromal cells (MSCs) are a promising therapeutic tool in cell therapy and tissue engineering because of their multi-lineage differentiation capacity, immunomodulatory effects, and tissue protective potential. To achieve optimal results as a therapeutic tool, factors affecting MSC potency, including but not limited to cell source, donor age, and cell batch, have been investigated. Although the sex of the donor has been attributed as a potential factor that can influence MSC potency and efficacy, the impact of donor sex on MSC characteristics has not been carefully investigated. In this review, we summarize published studies demonstrating donor-sex-related MSC heterogeneity and emphasize the importance of disclosing donor sex as a key factor affecting MSC potency in cell therapy.

Mesenchymal stromal/stem cell (MSC)-derived exosomes in clinical trials.

Mesenchymal stromal/stem cells (MSCs) are widely utilized in cell therapy because of their robust immunomodulatory and regenerative properties. Their paracrine activity is one of the most important features that contribute to their efficacy. Recently, it has been demonstrated that the production of various factors via extracellular vesicles, especially exosomes, governs the principal efficacy of MSCs after infusion in experimental models. Compared to MSCs themselves, MSC-derived exosomes (MSC-Exos) have provided significant advantages by efficiently decreasing unfavorable adverse effects, such as infusion-related toxicities. MSC-Exos is becoming a promising cell-free therapeutic tool and an increasing number of clinical studies started to assess the therapeutic effect of MSC-Exos in different diseases. In this review, we summarized the ongoing and completed clinical studies using MSC-Exos for immunomodulation, regenerative medicine, gene delivery, and beyond. Additionally, we summarized MSC-Exos production methods utilized in these studies with an emphasis on MSCs source, MSC-Exos isolation methods, characterization, dosage, and route of administration. Lastly, we discussed the current challenges and future directions of exosome utilization in different clinical studies as a novel therapeutic strategy.

Amphiphilic peptide-tagged N-cadherin forms radial glial-like fibers that enhance neuronal migration in injured brain and promote sensorimotor recovery.

The mammalian brain has very limited ability to regenerate lost neurons and recover function after injury. Promoting the migration of young neurons (neuroblasts) derived from endogenous neural stem cells using biomaterials is a new and promising approach to aid recovery of the brain after injury. However, the delivery of sufficient neuroblasts to distant injured sites is a major challenge because of the limited number of scaffold cells that are available to guide neuroblast migration. To address this issue, we have developed an amphiphilic peptide [(RADA)3-(RADG)] (mRADA)-tagged N-cadherin extracellular domain (Ncad-mRADA), which can remain in mRADA hydrogels and be injected into deep brain tissue to facilitate neuroblast migration. Migrating neuroblasts directly contacted the fiber-like Ncad-mRADA hydrogel and efficiently migrated toward an injured site in the striatum, a deep brain area. Furthermore, application of Ncad-mRADA to neonatal cortical brain injury efficiently promoted neuronal regeneration and functional recovery. These results demonstrate that self-assembling Ncad-mRADA peptides mimic both the function and structure of endogenous scaffold cells and provide a novel strategy for regenerative therapy.

The Intersection of Human and Veterinary Medicine-A Possible Direction towards the Improvement of Cell Therapy Protocols in the Treatment of Perianal Fistulas.

The effective treatment of perianal fistulizing Crohn's disease is still a challenge. Local administration of mesenchymal stromal cells (MSCs) is becoming a part of accepted treatment options. However, as a fledgling technique, it still can be optimized. A new trend in translational research, which is in line with "One Health" approach, bases on exploiting parallels between naturally occurring diseases affecting humans and companion animals. Canine anal furunculosis (AF) has been indicated as condition analogous to human perianal Crohn's disease (pCD). This narrative review provides the first comprehensive comparative analysis of these two diseases based on the published data. The paper also outlines the molecular mechanisms of action of MSCs which are likely to have a role in modulating the perianal fistula niche in humans, and refers them to the current knowledge on the immunomodulatory properties of canine MSCs. Generally, the pathogenesis of both diseases shares main determinants such as the presence of genetic predispositions, dysregulation of immune response and the relation to intestine microbiota. However, we also identified many aspects which should be further specified, such as determining the frequency of true fistulas formation in AF patients, elucidating the role of TNF and Th17 pathway in the pathogenesis of AF, or clarifying the role of epithelial-to-mesenchymal transition phenomenon in the formation of canine fistulae. Nevertheless, the available data support the hypothesis that the results from testing cell therapies in dogs with anal furunculosis have a significant translational value in optimizing MSC transplants procedures in pCD patients.

Mesenchymal stem cell-based therapy and exosomes in COVID-19: current trends and prospects.

Novel coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2. The virus causes an exaggerated immune response, resulting in a cytokine storm and acute respiratory distress syndrome, the leading cause of COVID-19-related mortality and morbidity. So far, no therapies have succeeded in circumventing the exacerbated immune response or cytokine storm associated with COVID-19. Mesenchymal stem cells (MSCs), through their immunomodulatory and regenerative activities, mostly mediated by their paracrine effect and extracellular vesicle production, have therapeutic potential in many autoimmune, inflammatory, and degenerative diseases. In this paper, we review clinical studies on the use of MSCs for COVID-19 treatment, including the salutary effects of MSCs on the pathophysiology of COVID-19 and the immunomodulation of the cytokine storm. Ongoing clinical trial designs, cell sources, dose and administration, and populations are summarized, and the paracrine mode of benefit is discussed. We also offer suggestions for optimizing MSC-based therapies, including genetic engineering, strategies for cell surface modification, nanotechnology applications, and combination therapies.

Stem cell therapies for autoimmune hepatitis.

Autoimmune hepatitis is a chronic inflammatory hepatic disorder which may cause liver fibrosis. Appropriate treatment of autoimmune hepatitis is therefore important. Adult stem cells have been investigated as therapies for a variety of disorders in latest years. Hematopoietic stem cells (HSCs) were the first known adult stem cells (ASCs) and can give rise to all of the cell types in the blood and immune system. Originally, HSC transplantation was served as a therapy for hematological malignancies, but more recently researchers have found the treatment to have positive effects in autoimmune diseases such as multiple sclerosis. Mesenchymal stem cells (MSCs) are ASCs which can be extracted from different tissues, such as bone marrow, adipose tissue, umbilical cord, and dental pulp. MSCs interact with several immune response pathways either by direct cell-to-cell interactions or by the secretion of soluble factors. These characteristics make MSCs potentially valuable as a therapy for autoimmune diseases. Both ASC and ASC-derived exosomes have been investigated as a therapy for autoimmune hepatitis. This review aims to summarize studies focused on the effects of ASCs and their products on autoimmune hepatitis.

Upper gastrointestinal tract involvement in the management of bariatric patients in the Kingdom of Saudi Arabia.

BACKGROUND: Preoperative esophagogastroduodenoscopy (EGD) may affect the management of bariatric patients although this is not consistent universally. The present prospective study evaluated the effect of preoperative EGD findings in obese Saudi patients, including upper digestive symptoms (UDS) and comorbidities, on their planned surgery. METHODS: From January 2018 to May 2019, we conducted a 4-center retrospective observational study to evaluate the endoscopic findings among Saudi patients aged 18-65 years with a body mass index (BMI) >40 kg/m2. Preoperative data included UDS, comorbidities, Helicobacter pylori (H. pylori) infection assessed during a histopathological examination, and EGD findings. RESULTS: 717 patients underwent EGDs, and 432 underwent bariatric surgery. The mean BMI was 44.3±6.3 kg/m2, and the mean age was 27.8±11.8 years. The overall UDS prevalence was 49%, with the most frequent being gastroesophageal reflux disease 54% (387/717), followed by dyspepsia 44% (315/717). H. pylori infection was detected in 287/672 (42.4%) patients. The total percentage of patients with normal EGD was 36% (258/717). A delayed bariatric procedure was performed in 15% of the patients for the following reasons: 2.3% had large polyps of >1 cm (either hyperplastic or cystic polyps); 1.62% had esophagitis grade C and D based on the Los Angeles classification; 0.7% had Barrett's esophagus; and 5.7% had peptic ulcer disease. CONCLUSIONS: Our findings confirmed that obesity carries a profound health burden with a significant impact on health expenditures. Routine preoperative EGD in the obese Saudi population appears to be mandatory to identify factors that may change, delay, or postpone the bariatric procedure.

Comparative study between human mesenchymal stem cells and etanercept as immunomodulatory agents in rat model of rheumatoid arthritis.

To compare human adipose tissue mesenchymal stem cells (AT-MSCs) and etanercept as immunomodulatory agents for collagen-induced arthritis (CIA). CIA was induced by rats' immunization with collagen type II (CII) in complete Freund's adjuvant in days 0 and 7. Before the onset of CIA, prevention group received five doses of AT-MSCS intraperitoneally. After establishment of arthritis, rats received either five doses of AT-MSCs or phosphate-buffered saline (PBS) intraperitoneally or six doses of etanercept subcutaneously. Clinical and histopathological evaluation were performed in all groups; serum levels of tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), and anti-collagen II were assessed by enzyme-linked immunosorbent assay (ELISA). A total percent of autoreactive T and regulatory T (Treg) cells were quantified using spleen immune histochemical analysis. AT-MSCs were able to delay the onset of CIA, suppress the ongoing clinical and histopathological signs, decrease serum levels of TNF-α and anti-collagen type II, and downregulate the autoreactive T cells as etanercept. AT-MSCs were more potent in Treg cells upregulation, producing high serum levels of IL10. AT-MSCs might have a therapeutic effect in CIA via their potency in immune cell education, representing an effective new promising approach in rheumatoid arthritis in human.

Antifibrotic Effect of Combination of Nilotinib and Stem Cell-Conditioned Media on CCl4-Induced Liver Fibrosis.

Liver fibrosis is the excessive extracellular matrix accumulation of proteins, such as collagen, which follows the chronic liver diseases. Advanced liver fibrosis leads to cirrhosis and liver failure. Nilotinib is a second-generation tyrosine kinase inhibitor, which showed antifibrotic efficacy. Stem cell therapy still has some limitations such as oncogenesis, unexpected differentiation, and ethical consideration. Stem cells secrete cytokines and growth factors that showed paracrine-mediated antifibrotic and anti-inflammatory effects in vivo and in vitro. Thus, stem cell-conditioned medium (SC-CM), which contains the secretory proteins of stem cells, may have an antifibrotic role. This study was carried out to examine the antifibrotic effect of Nilotinib and stem cell exosomes on CCl4-induced liver fibrosis in rats. Male Wistar rats were injected intraperitoneally with CCl4 twice a week for 9 weeks and given daily treatments of Nilotinib (20 mg/kg), stem cell exosomes (0.5 ml/rat), and the combination treatment of Nilotinib and stem cell exosomes during the last 5 weeks of CCl4 intoxication. Liver fibrosis and also antifibrotic efficacy of the treatments were estimated with liver function tests, oxidative stress parameters, apoptotic parameters, histopathological examination, and hydroxyproline contents. Results showed that the combination of Nilotinib and stem cell-conditioned media had more antifibrotic effects than each one alone (P value < 0.001).

Efficacy and Safety of Intraperitoneal Local Anesthetics in Laparoscopic Appendectomy: A Systematic Review and Meta-Analysis.

Intraperitoneal local anesthetics have been increasingly used nowadays. However, they are not routinely given in laparoscopic appendectomy and a lot of controversies are found about their administration in this procedure. The goal of this study is to review effectiveness and safety of intraperitoneal local anesthetics in laparoscopic appendectomy. We conducted a computer search of four authentic databases. We included randomized controlled trials (RCTs) which compared intraperitoneal local anesthetics versus control group in laparoscopic appendectomy. Data were extracted from eligible studies and pooled in a meta-analysis model using RevMan software. We evaluated post-operative pain in different periods and safety outcomes including postoperative nausea and vomiting (PONV) and shoulder pain. Furthermore, we assessed the length of hospital stay and postoperative opioid consumption within 24 hours. Seven RCTs were included with a total of 579 patients in this review. Our analysis indicated a significant difference in postoperative pain at different durations preferring intraperitoneal local anesthetics compared to control. Moreover, intraperitoneal local anesthetics were significantly linked to fewer patients experienced PONV and shoulder pain respectively (RR= 0.28, 95% CI [0.16, 0.50], p < 0.0001), (RR= 0.32, 95% CI [0.17, 0.58], p = 0.0002). We found less hospital stay duration in intraperitoneal local anesthetics group after removal of the heterogeneity (MD= -0.39, 95% CI [-0.63, -0.16], p = 0.001). Intraperitoneal local anesthetics were significantly linked to less postoperative opioid consumption (SMD = -0.60, 95% CI [-0.96, -0.24], p = 0.001). Intraperitoneal local anesthetics can be routinely used in laparoscopic appendectomy as it is associated with less postoperative pain and reduction in different adverse events postoperatively.

Mesenchymal stem cells as a treatment for multiple sclerosis: a focus on experimental animal studies.

Multiple sclerosis (MS) is a progressive and debilitating neurological condition in which the immune system abnormally attacks the myelin sheath insulating the nerves. Mesenchymal stem cells (MSCs) are found in most adult tissues and play a significant systemic role in self-repair. MSCs have promising therapeutic effects in many diseases, such as autoimmune diseases, including MS. MSCs have been tested in MS animal models, such as experimental autoimmune encephalomyelitis. Other studies have combined other agents with MSCs, genetically modified MSCs, or used culture medium from MSCs. In this review, we will summarize these studies and compare the main factors in each study, such as the source of MSCs, the type of animal model, the route of injection, the number of injected cells, and the mechanism of action.

Comparative study of biological characteristics of mesenchymal stem cells isolated from mouse bone marrow and peripheral blood.

Mesenchymal stromal cells (MSCs) possess self-renewal and multilineage differentiation potential, indicating their prospects as cellular therapeutic agents for regenerative medicine. Although adult bone marrow (BM) is the major source of these cells for clinical use, harvesting requires invasive procedures. Therefore, alternative sources, such as peripheral blood (PB), are needed. The objective of the current study was to compare PB-MSCs and BM-MSCs with regard to their biological characteristics. PB-MSCs and BM-MSCs were isolated from 4-week-old BALB/c white mice by density gradient centrifugation and cultured in DMEM + 10% fetal bovine serum until passage four. Morphological features, proliferation, cell surface marker expression and trilineage differentiation potential were assessed for both PB-MSCs and BM-MSCs. No significant differences in morphological features were observed. BM-MSCs had a higher proliferative capability than PB-MSCs as measured by XTT assays. Both PB-MSCs and BM-MSCs had broadly similar cell surface marker expression, but PB-MSCs had positive expression of cluster of differentiation (CD)146 and CD140b. Both PB-MSCs and BM-MSCs were capable of trilineage differentiation. Although BM-MSCs had a greater capacity for osteogenic and chondrogenic differentiation than PB-MSCs, PB-MSCs had a better capability for adipogenic differentiation than BM-MSCs. In conclusion, PB-MSCs and BM-MSCs have very similar biological characteristics. Thus, PB is a promising source for easily obtaining MSCs in mice.

Fluoxetine induces direct inhibitory effects on mesenchymal stem cell­derived osteoprogenitor cells independent of serotonin concentration.

Selective serotonin reuptake inhibitors are the most commonly prescribed antidepressants worldwide, which have been reported to exert potential detrimental effects on bone mineral density and increase the risk of developing fractures. The present study aimed to investigate the pathways underlying the negative effects of fluoxetine on bone using mesenchymal stem cells (MSCs) derived from rat adipose tissue as a source of osteoprogenitor cells. MSCs were harvested from adipose tissue using a collagenase enzyme digestion method and were allowed to differentiate into osteoprogenitor cells. Various concentrations of fluoxetine were added to the cells, which were harvested and analyzed by flow cytometry to detect apoptotic markers Annexin V and caspase­3, in order to assess the levels of apoptosis. The levels of endogenous serotonin released in the extracellular matrix were measured using a serotonin ELISA kit. The underlying molecular pathways associated with the effects of fluoxetine on bone were investigated with reverse transcription­quantitative polymerase chain reaction. The results of the present study revealed a significant dose­dependent increase in apoptosis in response to increasing doses of fluoxetine, which was independent of serotonin levels in the culture supernatant. These findings indicated that fluoxetine exerted a direct inhibitory effect on bone cells via an apoptosis­dependent pathway. Furthermore, the expression levels of serotonergic genes, including serotonin 1B receptor, serotonin 2A receptor (HTR2A), serotonin 2B receptor and serotonin transporter, were down regulated; of these genes, HTR2A exhibited the highest expression levels. Further in vitro and in vivo studies are required to verify this association and to determine the molecular pathways involved in fluoxetine­induced bone loss. Fluoxetine­induced apoptosis of osteoprogenitor cells may be the mechanism underlying the increased incidence of bone loss observed in patients treated with fluoxetine.

Role of ursodeoxycholic acid in the prevention of gallstone formation after laparoscopic sleeve gastrectomy.

PURPOSE: Postoperative cholelithiasis (CL) is a latent complication of bariatric surgery. The aim of this study was to evaluate the role of ursodeoxycholic acid (UDCA) in the prevention of CL after laparoscopic sleeve gastrectomy (LSG). METHODS: This was a retrospective analysis of the prospectively collected data of patients with morbid obesity who underwent LSG. Patients were subdivided into two groups: Group I, which did not receive prophylactic treatment with UCDA after LSG; and Group II, which received UCDA therapy for 6 months after LSG. Patients' characteristics, operation duration, weight loss data, and incidence of CL at 6 and 12 months postoperatively were collected. RESULTS: A total of 406 patients (124 males, 282 females) with a mean age of 32.1 ± 9.4 years were included. The mean baseline body mass index (BMI) was 50.1 ± 8.3 kg/m2. Group I comprised 159 patients, and Group II comprised 247 patients. The two groups showed comparable demographics, % excess weight loss (EWL), and decrease in BMI at 6 and 12 months after LSG. Eight patients (5%) developed CL in Group I, whereas no patients in Group II did (P = 0.0005). Preoperative dyslipidemia and rapid loss of excess weight within the first 3 months after LSG were the risk factors that significantly predicted CL postoperatively. CONCLUSION: The use of UCDA effectively reduced the incidence of CL after LSG in patients with morbid obesity. Dyslipidemia and rapid EWL in the first 3 months after LSG significantly predisposed patients to postoperative CL.

Mesenchymal stem cells growth and proliferation enhancement using PLA vs PCL based nanofibrous scaffolds.

Electrospinning of polymers is the most commonly used technique for nanofiber fabrication. polylactic acid (PLA) and polycaprolactone (PCL) have been shown to be ideal for nanofiber preparation in various biomedical applications, due to characteristics such as biodegradablity and their ability to promote the cell growth, similar to native tissues. The aim of this study was to develop biocompatible and biodegradable PLA and PCL-based nanofibrous scaffolds for enhancing stem cell growth and proliferation. The scaffolds were prepared by electrospinning, and their physicochemical properties were studied using Fourier Transform Infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and X-ray diffraction (XRD). The surface morphology of the developed scaffolds was determined using scanning electron microscopy (SEM). Mesenchymal stem cells (MSCs), derived from both adipose tissue and bone marrow, were seeded onto the prepared nanofibrous scaffolds. The effect of scaffold type, and structural characteristics on survival and proliferation of MSCs were evaluated. Our results show that after full physicochemical characterization of PCL and PLA nanofibrous scaffolds both were safe and non-toxic to the evaluated cells and both scaffolds supported cell attachment and proliferation of bone marrow and adipose tissue-derived MSCs.

Bilateral gluteal advancement flap for treatment of recurrent sacrococcygeal pilonidal disease: A prospective cohort study.

BACKGROUND: There is controversy about the best surgical approach for recurrent pilonidal disease (PND) up till now. This study aims to evaluate the efficacy of bilateral gluteal fascio-myo-cutaneous advancement flap (BGFMCF) in treatment of recurrent PND. PATIENT AND METHODS: Forty patients (35 males, 5 females) with recurrent PND were admitted and treated with BGFMCF. Variables assessed were incidence of recurrence, postoperative complications, patients' satisfaction and quality of life. RESULTS: Patients had a mean age of 25 ± 6.8 years and a mean body mass index of 28.4 ± 2.7. Mean operative time was 87 ± 13 min and mean length of hospital stay was 3 ± 0.7 days. Mean period of follow-up was 15.8 ± 4.9 months. Recurrence was detected in 2 (5%) patients and minor complications occurred in 6 (15%) patients. Thirty eight (95%) patients were satisfied by the procedure at the end of follow-up period. CONCLUSION: BGFMCF is an effective procedure for treatment of recurrent sacrococcygeal PND with low recurrence rate and acceptable morbidity.