Hypoxic Wharton’s Jelly Stem Cell Conditioned Medium Induces Immunogenic Cell Death in Lymphoma CellsRead the full article
Stem Cells International publishes papers in all areas of stem cell biology and applications. The journal publishes basic, translational, and clinical research, including animal models and clinical trials.
Chief Editor, Professor Li, has a background in cardiac stem cell transplantation, using young stem cells to promote tissue repair following injury to rejuvenate the aged individual, and the development of biomaterials that can easily integrate into damaged heart tissue.
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Enhanced Effect of IL-1β-Activated Adipose-Derived MSCs (ADMSCs) on Repair of Intestinal Ischemia-Reperfusion Injury via COX-2-PGE2 Signaling
Adipose-derived mesenchymal stem cells (ADMSCs) have been used for treating tissue injury, and preactivation enhances their therapeutic effect. This study is aimed at investigating the therapeutic effect of activated ADMSCs by IL-1β on the intestinal ischaemia-reperfusion (IR) injury and exploring potential mechanisms. ADMSCs were pretreated with IL-1β in vitro, and activation of ADMSCs was assessed by α-SMA and COX-2 expressions and secretary function. Activated ADMSCs was transplanted into IR-injured intestine in a mouse model, and therapeutic effect was evaluated. In addition, to explore underlying mechanisms, COX-2 expression was silenced to investigate its role in activated ADMSCs for treatment of intestinal IR injury. When ADMSCs were pretreated with 50 ng/ml IL-1β for 24 hr, expressions of α-SMA and COX-2 were significantly upregulated, and secretions of PGE2, SDF-1, and VEGF were increased. When COX-2 was silenced, the effect of IL-1β treatment was abolished. Activated ADMSCs with IL-1β significantly suppressed inflammation and apoptosis and enhanced healing of intestinal IR injury in mice, and these effects were impaired by COX-2 silencing. The results of RNA sequencing suggested that compared with the IR injury group activated ADMSCs induced alterations in mRNA expression and suppressed the activation of the NF-κB-P65, MAPK-ERK1/2, and PI3K-AKT pathways induced by intestinal IR injury, whereas silencing COX-2 impaired the suppressive effect of activated ADMSCs on these pathway activations induced by IR injury. These data suggested that IL-1β pretreatment enhanced the therapeutic effect of ADMSCs on intestinal IR injury repairing via activating ADMSC COX-2-PGE2 signaling axis and via suppressing the NF-κB-P65, MAPK-ERK1/2, and PI3K-AKT pathways in the intestinal IR-injured tissue.
RSP5 Positively Regulates the Osteogenic Differentiation of Mesenchymal Stem Cells by Activating the K63-Linked Ubiquitination of Akt
Mesenchymal stem cells (MSCs) are multipotent stem cells that have a strong osteogenic differentiation capacity. However, the molecular mechanism underlying the osteogenic differentiation of MSCs remains largely unknown and thus hinders further development of MSC-based cell therapies for bone repair in the clinic. RSP5, also called NEDD4L (NEDD4-like E3 ubiquitin protein ligase), belongs to the HECT (homologous to E6-AP carboxyl terminus) domain-containing E3 ligase family. Nevertheless, although many studies have been conducted to elucidate the role of RSP5 in various biological processes, its effect on osteogenesis remains elusive. In this study, we demonstrated that the expression of RSP5 was elevated during the osteogenesis of MSCs and positively regulated the osteogenic capacity of MSCs by inducing K63-linked polyubiquitination and activation of the Akt pathway. Taken together, our findings suggest that RSP5 may be a promising target to improve therapeutic efficiency by using MSCs for bone regeneration and repair.
Low-Dose Decitabine Assists Human Umbilical Cord-Derived Mesenchymal Stem Cells in Protecting β Cells via the Modulation of the Macrophage Phenotype in Type 2 Diabetic Mice
Background. Progressive β-cell dysfunction, a major characteristic of type 2 diabetes (T2D), is closely related to the infiltration of inflammatory macrophages within islets. Mesenchymal stem cells (MSCs) have been identified to alleviate β-cell dysfunction by modulating macrophage phenotype in T2D, but the restoration of β-cells by a single MSC infusion is relatively transient. Decitabine (DAC) has been reported to polarize macrophages towards the anti-inflammatory phenotype at low doses. We therefore investigated whether low-dose decitabine could enhance the antidiabetic effect of MSCs and further promote the restoration of β-cell function. Methods. We induced a T2D mice model by high-fat diets and streptozotocin (STZ) injection. Mice were divided into five groups: the normal group, the T2D group, the DAC group, the MSC group, and the MSC plus DAC group (MD group). We examined the blood glucose and serum insulin levels of mice 1, 2, and 4 weeks after MSC and/or DAC treatment. Dynamic changes in islets and the phenotype of intraislet macrophages were detected via immunofluorescence. In vitro, we explored the effect of MSCs and DAC on macrophage polarization. Results. The blood glucose and serum insulin levels revealed that DAC prolonged the antidiabetic effect of MSCs to 4 weeks in T2D mice. Immunofluorescence staining demonstrated more sustainable morphological and structural amelioration in islets of the MD group than in the MSC group. Interestingly, further analysis showed more alternatively activated macrophages (M2, anti-inflammatory) and fewer classically activated macrophages (M1, proinflammatory) in islets of the MD group 4 weeks after treatment. An in vitro study demonstrated that DAC together with MSCs further polarized macrophages from the M1 to M2 phenotype via the PI3K/AKT pathway. Conclusion. These data unveiled that DAC prolonged the antidiabetic effect of MSCs and promoted sustainable β-cell restoration, possibly by modulating the macrophage phenotype. Our results offer a preferable therapeutic strategy for T2D.
Clinical Efficacy and Safety of Mesenchymal Stem Cells for Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) is a polymorphic, multisystemic autoimmune disease that causes multiorgan damage in which cellular communication occurs through the involvement of autoantibodies directed against autoantigen production. Mesenchymal stem cells (MSCs), which have strong protective and immunomodulatory abilities, are obtained not only from bone marrow but also from medical waste such as adipose tissue and umbilical cord tissue and have been recognized as a promising tool for the treatment of various autoimmune diseases and inflammatory disorders. This meta-analysis is aimed at assessing whether MSCs can become a new treatment for SLE with good efficacy and safety. Based on predetermined criteria, a bibliographical search was performed from January 1, 2000, to July 31, 2019, by searching the following databases: ISI Web of Science, Embase, PubMed, the Cochrane Library, and the Chinese Biomedical Literature Database (CBM). Eligible studies and data were identified. Statistical analysis was conducted to assess the efficacy (proteinuria, systemic lupus erythematosus disease activity index (SLEDAI), Scr, BUN, albumin, C3, and C4) and safety (rate of adverse events) of MSCs for SLE using Cochrane Review Manager Version 5.3. Ten studies fulfilled the inclusion criteria and were eligible for this meta-analysis, which comprised 8 prospective or retrospective case series and four randomized controlled trails (RCTs) studies. In the RCT, the results indicated that the MSC group had lower proteinuria than the control group at 3 months and 6 months and the MSC group displayed a lower SLEDAI than the control group at 2 months and 6 months. Furthermore, the MSC group showed a lower rate of adverse events than the control group (, 95% CI: 0.07, 0.89, ). In the case series trials, the results indicated that the MSC group had lower proteinuria at 1 month, 2 months, 3 months, 4 months, 6 months, and 12 months. In conclusion, MSCs might be a promising therapeutic agent for patients with SLE.
Vitamin C Treatment Rescues Prelamin A-Induced Premature Senescence of Subchondral Bone Mesenchymal Stem Cells
Aging is a predominant risk factor for many chronic conditions. Stem cell dysfunction plays a pivotal role in the aging process. Prelamin A, an abnormal processed form of the nuclear lamina protein lamin A, has been reported to trigger premature senescence. However, the mechanism driving stem cell dysfunction is still unclear. In this study, we found that while passaging subchondral bone mesenchymal stem cells (SCB-MSCs) in vitro, prelamin A accumulation occurred concomitantly with an increase in senescence-associated β-galactosidase (SA-β-Gal) expression. Unlike their counterparts, SCB-MSCs with prelamin A overexpression (MSC/PLA) demonstrated decreased proliferation, osteogenesis, and adipogenesis but increased production of inflammatory factors. In a hind-limb ischemia model, MSC/PLA also exhibited compromised therapy effect. Further investigation showed that exogenous prelamin A triggered abnormal nuclear morphology, DNA and shelterin complex damage, cell cycle retardation, and eventually cell senescence. Changes in gene expression profile were also verified by microarray assay. Interestingly, we found that ascorbic acid or vitamin C (VC) treatment could inhibit prelamin A expression in MSC/PLA and partially reverse the premature aging in MSC/PLA, with reduced secretion of inflammatory factors and cell cycle arrest and resistance to apoptosis. Importantly, after VC treatment, MSC/PLA showed enhanced therapy effect in the hind-limb ischemia model. In conclusion, prelamin A can accelerate SCB-MSC premature senescence by inducing DNA damage. VC can be a potential therapeutic reagent for prelamin A-induced aging defects in MSCs.
Induced Pluripotent Stem Cells in Dental and Nondental Tissue Regeneration: A Review of an Unexploited Potential
Cell-based therapies currently represent the state of art for tissue regenerative treatment approaches for various diseases and disorders. Induced pluripotent stem cells (iPSCs), reprogrammed from adult somatic cells, using vectors carrying definite transcription factors, have manifested a breakthrough in regenerative medicine, relying on their pluripotent nature and ease of generation in large amounts from various dental and nondental tissues. In addition to their potential applications in regenerative medicine and dentistry, iPSCs can also be used in disease modeling and drug testing for personalized medicine. The current review discusses various techniques for the production of iPSC-derived osteogenic and odontogenic progenitors, the therapeutic applications of iPSCs, and their regenerative potential in vivo and in vitro. Through the present review, we aim to explore the potential applications of iPSCs in dental and nondental tissue regeneration and to highlight different protocols used for the generation of different tissues and cell lines from iPSCs.
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