Том 19, № 2 (2024)

Medicine

Meet the Editorial Board Member

De Carvalho K.
Current Stem Cell Research & Therapy. 2024;19(2):133-133
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Therapeutic Potential of Mesenchymal Stem Cells in PCOS

Nejabati H., Nikzad S., Roshangar L.

Аннотация

Polycystic ovary syndrome (PCOS) is a major reproductive endocrine disorder affecting different facets of a woman’s life, comprising reproduction, metabolism, and mental health. Recently, several research groups have brought attention to the therapeutic capacity of mesenchymal stem cells (MSCs) for the treatment of female reproductive disorders. It is highlighted that the treatment with bone marrow mesenchymal stem cells (BMMSCs) considerably diminishes the levels of some inflammatory markers as well as essential genes for ovarian production of androgens, which are considerably higher in theca cells of PCOS women than in those of healthy cases. In addition, studies show that BMMSCs improve in vitro maturation (IVM) of germinal vesicles (GVs) and the number of antral follicles while lessening the number of primary and preantral follicles in mice with PCOS compared to healthy controls. Regarding adipose- derived mesenchymal stem cells (AdMSCs), these cells restore the ovarian structure, enhance the number of oocytes and corpora luteum, and diminish the number of aberrant cystic follicles in PCOS rats. Some research also indicates that umbilical cord mesenchymal stem cells (UC-MSCs) alleviate the inflammation of granulosa cells in women with PCOS. Therefore, due to the limited research on MSC therapy in PCOS, in this review, we summarize the current knowledge on the therapeutic potential of three types of MSCs: BMMSCs, AdMSCs, UC-MSCs and their secretome in the treatment of PCOS.

Current Stem Cell Research & Therapy. 2024;19(2):134-144
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Effector Proteins of Type IV Secretion System: Weapons of Brucella Used to Fight Against Host Immunity

Zheng M., Lin R., Zhu J., Dong Q., Chen J., Jiang P., Zhang H., Liu J., Chen Z.

Аннотация

:Brucella is an intracellular bacterial pathogen capable of long-term persistence in the host, resulting in chronic infections in livestock and wildlife. The type IV secretion system (T4SS) is an important virulence factor of Brucella and is composed of 12 protein complexes encoded by the VirB operon. T4SS exerts its function through its secreted 15 effector proteins. The effector proteins act on important signaling pathways in host cells, inducing host immune responses and promoting the survival and replication of Brucella in host cells to promote persistent infection. In this article, we describe the intracellular circulation of Brucella-infected cells and survey the role of Brucella VirB T4SS in regulating inflammatory responses and suppressing host immune responses during infection. In addition, the important mechanisms of these 15 effector proteins in resisting the host immune response during Brucella infection are elucidated. For example, VceC and VceA assist in achieving sustained survival of Brucella in host cells by affecting autophagy and apoptosis. BtpB, together with BtpA, controls the activation of dendritic cells during infection, induces inflammatory responses, and controls host immunity. This article reviews the effector proteins secreted by Brucella T4SS and their involvement in immune responses, which can provide a reliable theoretical basis for the subsequent mechanism of hijacking the host cell signaling pathway by bacteria and contribute to the development of better vaccines to effectively treat Brucella bacterial infection.

Current Stem Cell Research & Therapy. 2024;19(2):145-153
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Signaling Pathways in Drosophila gonadal Stem Cells

Eslahi M., Nematbakhsh N., Dastmalchi N., Teimourian S., Safaralizadeh R.

Аннотация

The stem cells' ability to divide asymmetrically to produce differentiating and self-renewing daughter cells is crucial to maintain tissue homeostasis and development. Stem cell maintenance and differentiation rely on their regulatory microenvironment termed ‘niches’. The mechanisms of the signal transduction pathways initiated from the niche, regulation of stem cell maintenance and differentiation were quite challenging to study. The knowledge gained from the study of Drosophila melanogaster testis and ovary helped develop our understanding of stem cell/niche interactions and signal pathways related to the regulatory mechanisms in maintaining homeostasis of adult tissue. In this review, we discuss the role of signaling pathways in Drosophila gonadal stem cell regeneration, competition, differentiation, dedifferentiation, proliferation, and fate determination. Furthermore, we present the current knowledge on how these signaling pathways are implicated in cancer, and how they contribute as potential candidates for effective cancer treatment.

Current Stem Cell Research & Therapy. 2024;19(2):154-165
pages 154-165 views

The Role of Various Factors in Neural Differentiation of Human Umbilical Cord Mesenchymal Stem Cells with a Special Focus on the Physical Stimulants

Seyyedin S., Ezzatabadipour M., Nematollahi-Mahani S.

Аннотация

Human umbilical cord matrix-derived mesenchymal stem cells (hUCMs) are considered as ideal tools for cell therapy procedures and regenerative medicine. The capacity of these cells to differentiate into neural lineage cells make them potentially important in the treatment of various neurodegenerative diseases. An electronic search was performed in Web of Science, PubMed/MEDLINE, Scopus and Google Scholar databases for articles published from January 1990 to March 2022. This review discusses the current knowledge on the effect of various factors, including physical, chemical and biological stimuli which play a key role in the differentiation of hUCMs into neural and glial cells. Moreover, the currently understood molecular mechanisms involved in the neural differentiation of hUCMs under various environmental stimuli are reviewed. Various stimuli, especially physical stimuli and specifically different light sources, have revealed effects on neural differentiation of mesenchymal stem cells, including hUCMs; however, due to the lack of information about the exact mechanisms, there is still a need to find optimal conditions to promote the differentiation capacity of these cells which in turn can lead to significant progress in the clinical application of hUCMs for the treatment of neurological disorders.

Current Stem Cell Research & Therapy. 2024;19(2):166-177
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New Concepts in the Manipulation of the Aging Process

Hollands P., Ovokaitys T.

Аннотация

This review explores the current concepts in aging and then goes on to describe a novel, ground-breaking technology which will change the way we think about and manage aging. The foundation of the review is based on the work carried out on the QiLaser activation of human Very Small Embryonic Like (hVSEL) pluripotent stem cells in autologous Platelet Rich Plasma (PRP), known as the Qigeneration Procedure. The application of this technology in anti-aging technology is discussed with an emphasis on epigenetic changes during aging focusing on DNA methylation.

Current Stem Cell Research & Therapy. 2024;19(2):178-184
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Stem Cell Therapy for the Treatment of Parkinson's Disease: What Promise Does it Hold?

Nasrolahi A., Shabani Z., Sadigh-Eteghad S., Salehi-Pourmehr H., Mahmoudi J.

Аннотация

Parkinson's disease (PD) is a common, progressive neurodegenerative disorder characterized by substantia nigra dopamine cell death and a varied clinical picture that affects older people. Although more than two centuries have passed since the earliest attempts to find a cure for PD, it remains an unresolved problem. With this in mind, cell replacement therapy is a new strategy for treating PD. This novel approach aims to replace degenerated dopaminergic (DAergic) neurons with new ones or provide a new source of cells that can differentiate into DAergic neurons. Induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), and embryonic stem cells (ESCs) are among the cells considered for transplantation therapies. Recently disease-modifying strategies like cell replacement therapies combined with other therapeutic approaches, such as utilizing natural compounds or biomaterials, are proposed to modify the underlying neurodegeneration. In the present review, we discuss the current advances in cell replacement therapy for PD and summarize the existing experimental and clinical evidence supporting this approach.

Current Stem Cell Research & Therapy. 2024;19(2):185-199
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The Beneficial Effects of Mesenchymal Stem Cells in Acute Kidney Injury: A Narrative Review

Liu Y., Han J., Fang J., Li R.

Аннотация

Background:Acute kidney injury (AKI) is a multifaced disease characterized by a rapid decline in renal function. However, with growing insight into the pathophysiologic mechanisms of AKI, currently available interventions for AKI are merely supportive. Thus, novel therapies are urgently needed to improve the outcomes of patients with AKI. This narrative review aims to explore enhancing the beneficial effects of Mesenchymal Stem Cells(MSCs) in AKI.

Methods:The authors examined all studies regarding the role of MSCs in AKI. And the authors undertook a structured search of bibliographic databases for peer-reviewed research literature using a focused review question. The most relevant and up-to-date research was included.

Results and Discussion:Based on encouraging preclinical results, stem cell therapy has been widely explored over the last decade. Among the various stem cell types investigated, mesenchymal stem cells are being intensely investigated by virtue of their numerous strengths, such as easy derivation, undemanding cell culture conditions, anti-apoptosis, immunomodulation, and anti-inflammation effects. Mounting evidence suggests that MSCs hold great potential in accelerating kidney repair following AKI in various preclinical models. Unfortunately, low engrafting efficiency and poor survival rate of injected MSCs in the injured renal tissue are major obstacles MSCs clinical application faces.

Conclusion:Various strategies, including genetic manipulation, mimicking the cellular microenvironment with different culture conditions, optimizing MSCs preparation and administration schedule, and screening patients who may more like benefit from MSCs therapy, have been developed to enhance the therapeutic potential of MSCs in AKI.

Current Stem Cell Research & Therapy. 2024;19(2):200-209
pages 200-209 views

Stem Cell Treatment and Cerebral Palsy: A Systematic Review and Meta-Analysis

Motavaf M., Dehghan S., Ghajarzadeh M., Ebrahimi N., Zali A., Safari S., Mirmosayyeb O.

Аннотация

Objective:We designed this systematic review and meta-analysis to estimate the pooled efficacy and safety profile of different types of stem cells in treating patients with cerebral palsy (CP).

Methods:We systematically searched PubMed, Scopus, EMBASE, Web of Science, Google Scholar, and also gray literature, including references of the included studies which were published before November 2021. We extracted data regarding the total number of participants, first author, publication year, country of origin, mean age, cell type, cell dose, cell source, method of transplantation, duration of follow-up, Gross motor function, Ashworth scale, and adverse events.

Results:We found 2073 articles by literature search; after deleting duplicates, 1194 remained. Nine articles remained for meta-analysis. The SMD of GMF-66 score (after-before) treatment was 1.5 (95% CI:0.7-2.3) (I2 = 89.9%, p < 0.001). The pooled incidence of Gastrointestinal (GI) complications after transplantation was 21% (95% CI:9-33%) (I2 = 56%, P = 0.08). The pooled incidence of fever after transplantation was 18 % (95% CI:6-30%) (I2 = 87.9%, P = 0.08 < 0.001)

Conclusion:The result of this systematic review and meta-analysis show that stem cell therapy in cerebral palsy has neuroprotective properties from anti-inflammatory and anti-apoptotic activities. Stem cell therapy seems to be a promising adjunct to traditional therapies for cerebral palsy patients.

Current Stem Cell Research & Therapy. 2024;19(2):210-219
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Preclinical Evidence for the Effectiveness of Mesenchymal Stromal Cells for Diabetic Cardiomyopathy: A Systematic Review and Meta-analysis

Liu B., Zhang J., Zhou Z., Feng B., He J., Yan W., Zhou X., Amponsah A., Guo R., Du X., Liu X., Cui H., O'Brien T., Ma J.

Аннотация

Background:Diabetic cardiomyopathy (DCM) is a complication of diabetes mellitus that endangers human health. DCM results in cardiac dysfunction, which eventually progresses to heart failure. Mesenchymal stromal cells (MSCs), a type of multipotent stem cell, have shown promising therapeutic effects in various cardiovascular diseases and diabetic complications in preclinical studies due to their immunomodulatory and regenerative abilities. However, there is still a lack of evidence to summarize the effectiveness of MSCs in the treatment of DCM. Therefore, a meta-analysis and systematic review are warranted to evaluate the therapeutic potential of MSCs for DCM in preclinical studies.

Methods:A comprehensive literature search in English or Chinese was conducted in PubMed, EMBASE, web of Science, Cochrane Library, and China National Knowledge Internet from inception to June 30, 2022. The summarized outcomes included echocardiography, morphology, and pathology. Data were independently extracted and analyzed by two authors. The software we adopted was Review Manager5.4.1. This systematic review was written in compliance with PRISMA 2020 and the review protocol was registered on PROSPERO, registration no. CRD42022350032.

Results:We included 20 studies in our meta-analysis to examine the efficacy of MSCs in the treatment of DCM. The MSC-treated group showed a statistically significant effect on left ventricular ejection fraction (WMD=12.61, 95% CI 4.32 to 20.90, P=0.003) and short axis fractional shortening (WMD=6.84, 95% CI 4.09 to 9.59, p < 0.00001). The overall effects on the ratio of early to late diastolic mitral annular velocity, left ventricular end-diastolic pressure, maximum positive pressure development, maximum negative pressure development, left ventricular relaxation time constant, heart weight to body weight ratio, fibrosis area, and arteriole density were analyzed, suggesting that MSCs represent an effective therapy for the treatment of DCM.

Conclusion:Our results suggest a therapeutic role for MSCs in the treatment of DCM, and these results provide support for the use of MSCs in clinical trials of patients with DCM.

Current Stem Cell Research & Therapy. 2024;19(2):220-233
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Human Umbilical Cord Mesenchymal Stem Cells Alleviate Rat Knee Osteoarthritis via Activating Wnt/ β-catenin Signaling Pathway

Zhou Y., Zhao Y., Wu Y., Chen J., Wu H., Wei W., Yan S.

Аннотация

Background:Osteoarthritis (OA) is a chronic disease characterized by joint cartilage degeneration, destruction, and osteogenic hyperplasia. Human umbilical cord mesenchymal stem cells (hUCMSCs) have attracted increasing research interest due to their high clonogenic, proliferative, and migratory potential, as well as their improved secretion of relevant chondrogenic factors. This study evaluated the therapeutic potential and underlying mechanism of hUC-MSCs in alleviating pathological symptoms of OA.

Methods:For the in vivo study, OA rats were established by the Hulth method to observe the therapeutic effect of intra-articular injection of hUC-MSCs. X-ray tests, gross observations, and histological and immunohistochemical assessments were conducted in rats. Levels of interleukin-1 beta (IL-1β), IL-6, matrix metalloproteinase-13 (MMP-13), and tissue inhibitor matrix metalloproteinase-1 in rats’ synovial fluid were measured using enzyme-linked immunosorbent assay kits. For the in vitro study, hUC-MSCs and chondrocytes were cultured to explore the effect and underlying mechanisms of hUC-MSCs on OA. Apoptosis, proliferation, and glycosaminoglycan (GAG) were measured in the chondrocytes. The relative expression of aggrecan, COL-2, and SOX-9 mRNA was quantified by real-time polymerase chain reaction. Expressions of Wnt/β-catenin signaling molecules were measured by Western blot.

Results:We found that intra-articular injection of hUC-MSCs reduced the combined score, increased the expression of collagen II, and decreased the expression of MMP-13, IL-1β, and IL-6 in rat knee joints. Additionally, hUC-MSCs increased the content of GAGs, inhibited chondrocyte apoptosis, and promoted chondrocyte proliferation. The expression of aggrecan, COL-2, and SOX-9 mRNA in chondrocytes was promoted by hUC-MSCs via activation of the Wnt/β-catenin signaling pathway.

Conclusion:Overall, this study demonstrated that hUC-MSCs induce the secretion of some cytokines via the paracrine function to activate the Wnt/β-catenin signaling pathway to reduce the pathological condition of OA and maintain the proper expression of cytokines and extracellular matrix proteins.

Current Stem Cell Research & Therapy. 2024;19(2):234-244
pages 234-244 views

Mesenchymal Stem Cell-derived Type II Alveolar Epithelial Progenitor Cells Attenuate LPS-induced Acute Lung Injury and Reduce P63 Expression

Ma N., Zhang M., Xu G., Zhang L., Luo M., Luo M., Wang X., Tang H., Wang X., Liu L., Zhong X., Feng J., Li Y.

Аннотация

Aim:Acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) is a severe clinical respiratory-failure disease mainly characterized by acute damage to the alveolar epithelium and pulmonary vascular endothelial cells. Stem cell therapy has emerged as a potential regenerative strategy for ARDS/ALI, however, the outcome is limited, and the underlying mechanisms are unclear.

Introduction:We established a differentiation system for bone marrow-derived mesenchymal stem cellderived (BM-MSC) type II alveolar epithelial progenitor cells (AECIIs) and assessed their regulatory effects on lipopolysaccharide (LPS)-induced ALI.

Methods:We induced BM-MSC differentiation into AECIIs using a specific conditioned medium. After 26 days of differentiation, 3×105 BM-MSC-AECIIs were used to treat mice with LPS-induced ALI through tracheal injection.

Results:After tracheal injection, BM-MSC-AECIIs migrated to the perialveolar area and reduced LPSinduced lung inflammation and pathological injury. RNA-seq suggested that P63 protein was involved in the effects of BM-MSC-AECIIs on lung inflammation.

Conclusion:Our results suggest that BM-MSC-AECIIs may reduce LPS-induced acute lung injury by decreasing P63 expression.

Current Stem Cell Research & Therapy. 2024;19(2):245-256
pages 245-256 views

RADA-16-based Self-assembled Peptide Nanofiber Scaffolds Loaded with TGF-β1 Enhance the Chondrogenic Differentiation Potential of BMSCs In vitro

Yu P., Duan L., Yan Z., Li J., Cai D.

Аннотация

Objective:At present, cartilage repair does not offer ideal efficacy. Fortunately, recent studies have claimed that RADA-16 peptide is an attractive therapeutic strategy for repairing cartilage defects. Therefore, this study tried to explore the effect of RADA-16 loaded with transforming growth factor-beta (TGF-β) 1 on cartilage differentiation of bone marrow mesenchymal stem cells (BMSCs).

Methods:First, the RADA-16 peptide was synthesized by solid phase peptide, and a well-defined hydrogel was formed by supramolecular peptide self-assembly. Then, TGF-β1 (loading concentration of 10 ng/mL) was loaded into RADA-16, with scanning electron microscopy to observe the morphology of the TGF-β1/RADA-16 hydrogel and detect its related properties. Next, BMSCs were isolated from bone marrow samples and identified. TGF-β1/RADA-16 was co-cultured with L929, BMSCs, and C28/I2 cells, respectively, and the survival and proliferation ability of the cells was determined by live/dead cell staining and MTT assay. Chondrogenic differentiation and sGAG production of BMSCs were determined by Alcian blue staining and Blyscan assay, the expression of cartilage-associated genes by qRT-PCR, and the levels of inflammatory factors by ELISA. As for mechanism investigation, the Smad and ERK/MAPK signaling pathways were detected by western blot.

Results:RADA-16 hydrogel exhibited a well-distributed and interconnected porous surface structure, with a loading rate of 91.9% for TGF-β1. The TGF-β1/RADA-16 hydrogel had good release and degradation properties, and had no negative effect on the survival and proliferation ability of BMSCs, L929, and C28/I2 cells. Importantly, TGF-β1/RADA-16 hydrogel significantly accelerated chondrogenic differentiation and sGAG generation in BMSCs, and decreased pro-inflammatory factor production. In addition, the hydrogel also significantly activated the Smad and ERK/MAPK pathways of BMSCs.

Conclusion:RADA-16 loaded with TGF-β1 has good biological properties and can enhance the chondrogenic differentiation ability of BMSCs.

Current Stem Cell Research & Therapy. 2024;19(2):257-266
pages 257-266 views

Total Saponins of Panax Notoginseng Modulate the Astrocyte Inflammatory Signaling Pathway and Attenuate Inflammatory Injury Induced by Oxygen- Glucose Deprivation/Reperfusion Injury in Rat Brain Microvascular Endothelial Cells

Wei X., Wen Y., Hu Y., Guo X.

Аннотация

Objective:Reperfusion after cerebral ischemia causes brain injury. Total saponins of Panax notoginseng (PNS) have potential roles in protecting against cerebral ischemia-reperfusion injury. However, whether PNS regulates astrocytes on oxygen-glucose deprivation/reperfusion (OGD/R) injury in rat brain microvascular endothelial cells (BMECs) and its mechanism still need further clarification.

Methods:Rat C6 glial cells were treated with PNS at different doses. Cell models were established by exposing C6 glial cells and BMECs to OGD/R. Cell viability was assessed, and levels of nitrite concentration, inflammatory factors (iNOS, IL-1β, IL-6, IL-8, TNF-α), and oxidative stress-related factors (MDA, SOD, GSH-Px, T-AOC) were subsequently measured through CCK8, Grice analysis, Western blot, and ELISA, respectively. The co-cultured C6 and endothelial cells were treated with PNS for 24 hours before model establishment. Then transendothelial electrical resistance (TEER), lactate dehydrogenase (LDH) activity, brain-derived neurotrophic factor (BDNF) content, and mRNA and protein levels and positive rates of tight junction proteins [Claudin-5, Occludin, ZO-1] were measured by a cell resistance meter, corresponding kits, ELISA, RT-qPCR, Western blot, and immunohistochemistry, respectively.

Results:PNS had no cytotoxicity. PNS reduced iNOS, IL-1β, IL-6, IL-8, and TNF-α levels in astrocytes, promoted T-AOC level and SOD and GSH-Px activities, and inhibited MDA levels, thus inhibiting oxidative stress in astrocytes. In addition, PNS alleviated OGD/R injury, reduced Na-Flu permeability, and enhanced TEER, LDH activity, BDNF content, and levels of tight junction proteins Claudin-5, Occludin, ZO-1 in the culture system of astrocytes and rat BMECs after OGD/R.

Conclusion:PNS repressed astrocyte inflammation and attenuated OGD/R injury in rat BMECs.

Current Stem Cell Research & Therapy. 2024;19(2):267-276
pages 267-276 views