Stem Cells International最新文献

Background: Nonalcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease and is a comorbidity in type 2 diabetes (T2D) mellitus. Mesenchymal stem cell (MSC) is emerging as a potential therapeutic strategy for diabetes and NAFLD through mitochondrial transfer initiated by signaling from injured recipient cells. Thus, in this study, we investigated whether exogenous mitochondrial preconditioning of MSCs could exert superior effects on NAFLD and explore the role of MSCs-mediated mitochondrial transfer into hepatocyte. Methods: After free HepG2 mitochondria pretreated, umbilical cord-derived MSCs (UC-MSCs) (mito-MSCs), T2D model mice were infused with equal amounts of MSCs/mito-MSCs via the tail vein once a week for 4 weeks. Body weight and random blood glucose were monitored weekly. After the end of treatment, the mitochondrial transfer level of MSCs before and after pretreatment were monitored by fluorescence tracing. Blood and liver were collected for biochemical and histopathological examinations. The number, morphology, and function of mitochondria in liver tissue were evaluated by tissue electron microscopy and western blot analysis. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to monitor the expression of genes associated with lipid metabolism and regulation pathways. Results: Pretreatment of UC-MSCs enhanced the efficacy of MSCs in lowering blood glucose, liver transaminase, triglyceride levels, and reducing histological damage, which may be related to free mitochondria triggering autophagy of MSCs, which in turn promoted the entry of MSCs mitochondria into the liver tissue of diabetic mice. Conclusion: Exogenous mitochondria could enhance the therapeutic efficacy of MSCs in NAFLD via mediating mitochondrial transfer, which offers a novel strategy for the improving the outcomes of MSCs cell-therapy for diabetes-related NAFLD.

Acute and chronic neurodegenerative conditions (NDs) are major causes of disability and mortality worldwide. Acute NDs encompass conditions such as stroke, traumatic brain injury (TBI), and spinal cord injury (SCI). On the other hand, chronic NDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). Currently, no definitive cure exists for these diseases, and available therapies focus primarily on slowing the progression of symptoms. Mesenchymal stem cells (MSCs), due to their multilineage differentiation capacity, immunomodulatory abilities, and regenerative properties, have gained attention in regenerative medicine. In recent years, extracellular vesicles (EVs) derived from MSCs have shown great promise as a cell-free therapeutic approach, eliminating the risks associated with direct MSCs use, such as tumorigenicity and poor cell survival after transplantation. EVs have emerged as powerful mediators of intercellular communication and tissue repair, exhibiting immunomodulatory, anti-inflammatory, and proregenerative properties. However, limitations such as low EVs yield and reduced efficacy due to MSCs replicative senescence restrict their therapeutic potential. Preconditioning strategies, including hypoxia, 3D cultures, and biochemical priming, have been explored in other fields to enhance EVs properties, yet their specific application to NDs remains under-reported. This review aims to address this gap by analyzing the preconditioning methods used to boost the therapeutic potential of MSCs-derived EVs for neurodegenerative diseases. These preconditioning strategies may enhance EVs yield, functional cargo, and targeted therapeutic efficacy for treating acute and chronic NDs.

Aims: Inflammation is a key process involved in the early stages of periodontal regeneration, where immune cells are responsible for the recruitment of osteoblast to facilitate periodontal regeneration. The aim of the present study was to explore the effect of platelet-rich fibrin (PRF) on macrophage polarization, and thereafter to investigate its effect on osteoblast recruitment to enhance early-stage periodontal regeneration. Materials and Methods: The extracted liquids of PRF, produced using fixed-angled and horizontal centrifugation protocols, were utilized to stimulate Thp1 to study macrophage proliferation and polarization. Thereafter, the supernatants of Thp1 were collected and utilized to stimulate the migration of human bone marrow osteoblasts, to investigate the recruitment of osteoblast via macrophage polarization. Results: PRF stimulated the proliferation and recruitment of macrophages, with horizontal centrifugation protocols demonstrating significantly greater potential when compared to fixed-angled. Furthermore, PRF was able to enhance the recruitment of osteoblast via macrophage polarization, with horizontal platelet-rich fibrin (H-PRF) demonstrating the most significant increase. Conclusion: The present study explored a promising mechanism of the periodontal regeneration function of PRF, by inducing macrophage polarization, thereby enhancing osteoblast recruitment, with horizontal centrifugation significantly improving these findings.

Cardiac fibroblasts (CFs) are activated into cardiac myofibroblasts (CMFs) in myocardial infarction (MI) and promote fibrosis, playing a crucial role in deteriorating cardiac function and inducing fatal arrhythmias. Transplantation of bone marrow mesenchymal stem cells (BMSCs) has emerged as a promising therapeutic approach for ischemic heart diseases, including MI. Recent studies have indicated that BMSCs can modulate the survival, differentiation, and antifibrotic activity of CFs. Kruppel-like factor 5 (KLF5) is a significant transcription factor involved in maintaining stem cell properties. In this study, we aimed to investigate whether overexpression of KLF5 could enhance the cardioprotective characteristics of BMSCs, particularly in terms of mitigating structural and electrical remodeling. Our in vivo experiments revealed that transplantation of KLF5-overexpressing BMSCs in mice with MI led to a substantial reduction in ventricular fibrosis and the occurrence of ventricular arrhythmias (VAs). In vitro coculture experiments demonstrated that BMSCs could inhibit CFs activation and cytoskeleton protein bundling induced by hypoxia through paracrine effects, resulting in reduced expression of α-SMA and Collagen I. Furthermore, coculturing BMSCs significantly reduced the expression of connexin 43, alleviated hypoxia, increased the expression of inward-rectifier K⁺ current (Kir), and decreased voltage-dependent K⁺ (Kv) currents. Mechanistically, KLF5 enhanced the effects of BMSCs by facilitating the transfer of miR-152-3 p from BMSCs-derived exosomes to CFs. Overall, our findings show that BMSCs transplantation promotes the recovery of cardiac function and reduces the incidence of arrhythmias by inhibiting CFs activation and modulating CFs Kir current remodeling. Additionally, overexpression of KLF5 enhances the cardioprotective effects of BMSCs.

Lacrimal gland (LG) dysfunction diseases are a type of disorder caused by various etiologies that damage the LG tissue, reducing lacrimal fluid secretion, triggering aqueous-deficient dry eye (ADDE), and causing a series of complications like keratoconjunctivitis sicca, potentially threatening vision. Our review summarizes the limitations and new progress of traditional treatment methods for LG dysfunction diseases. Meanwhile, we conduct in-depth analyses closely centered on the two emerging and cutting-edge research hotspots, namely stem cell therapy and organoid therapy. We have comprehensively evaluated the current research status regarding various stem cells, their derived extracellular vesicles, and LG organoid transplantation, further discussed the existing deficiencies, and subsequently put forward the prospective directions for future research. These include developing ophthalmic preparations of extracellular vesicles and LG stem cells or searching more efficient drug delivery systems, as well as culturing LG organoids that are highly similar to human lacrimal glands (LGs) in both function and microstructure through magnetic three-dimensional (3D) bioprinting technology and microfluidic 3D bioprinting technology.

Exosomes are naturally occurring cellular products released by various cell types in the body. Their composition is similar to that of human tissues, which reduces the risk of immune rejection. As critical mediators of intercellular communication, exosomes transmit signals and information that regulate the physiological states of surrounding tissues. Depending on their cellular origin and molecular content, exosomes can either promote nerve regeneration and functional recovery at the site of spinal cord injury (SCI) or exacerbate the local injury microenvironment. However, as a cellular product, the composition and function of exosomes are affected by the type and state of the cells from which they originate, and thus, there may be specificity problems in treatment, such as the possible instability of the therapeutic effect, et cetera. Moreover, exosomes need to be further optimized in terms of their delivery and release strategies in order to improve the duration and stability of the therapeutic effect. Thus, a single therapy approach is often insufficient to effectively support nerve repair following SCI. Numerous studies have demonstrated that encapsulating exosomes within biomaterial scaffolds enhances their delivery and retention at the injury site, thereby improving their viability. This paper reviews the latest research on stem cell-derived exosomes and biomaterials in the context of SCI. It further explores the combined application of exosomes and biomaterial scaffolds in SCI treatment, while also addressing the associated challenges and future prospects.

Lyme disease (LD), a zoonotic infectious disease caused by Borrelia burgdorferi (B. burgdorferi), can affect various organs, including the skin, heart, nervous system, and joints. Lyme arthritis (LA) is the most common and severe late-stage presentation of LD, often presenting with intermittent joint swelling and pain. Although antibiotics are effective in most patients with LA, some patients may continue to experience arthritis symptoms for months or years after standard treatment, which poses a serious threat to their quality of life. Therefore, more effective treatments are urgently needed. The purpose of this study was to evaluate the therapeutic effects of human umbilical cord mesenchymal stem cells (hUC-MSCs) on LD in Kunming (KM) mice. A bilateral hind limb LA model was established by infecting KM mice with B. burgdorferi. Low and high doses of hUC-MSCs (1 × 10⁶ and 2 × 10⁶ cells, respectively) were injected (one time every 2 days) into the right tibiotalar joints of the mice, whereas the left tibiotalar joints were pricked without injecting cells (sham operation). The therapeutic effects of the hUC-MSCs were evaluated through morphological examination, measurement of hind limb diameter, imaging assessment (X-ray), and measurement of inflammatory factor levels. Spirochete burden was assessed by quantitative real-time polymerase chain reaction (qPCR). Morphological, hind limb diameter, and imaging analyses showed that the low and high hUC-MSC doses significantly reduced bilateral hind limb swelling in the LA mice. Histological (hematoxylin and eosin staining) examination of tibiotalar joint sections showed that when compared with the control group, inflammatory cell infiltration, and bilateral hind limb tissue damage were reduced in the two treatment groups. Enzyme-linked immunosorbent assays revealed that the levels of IL-6 and TNF-α in lysates from the bilateral tibiotarsal joints were significantly lower in the two treatment groups than in the control group. QPCR results showed that hUC-MSCs treatment had no significant effect on the spirochete load in the tibiotarsal joint. Our findings indicate that hUC-MSCs can alleviate inflammation in the KM mouse model of LA without increasing B. burgdorferi burden., which is expected to be a new potential method for the treatment of LA.

Circadian rhythm abnormalities due to sleep deprivation (SD) may promote the development of emotional and cognitive disorders. Though light therapies have been employed to treat circadian disorders, the exact treatments and their underlying biology are still unclear. Our study aimed to investigate the effects of intrinsically photosensitive retinal ganglion cells (ipRGCs) sensitive 480 nm blue light on circadian rhythms affecting emotional and cognitive behaviors and the expression of neural stem cells (NSCs) stemness genes. In this study, we demonstrate that for mice with acute SD for 24 h, exposure to ipRGCs sensitive 480 nm blue light at ~ 1300 lux for 30 min at 8:00 a.m. and 8:00 p.m. improves the stability of disrupted clock genes, increases nocturnal activity, reduces anxiety-like behaviors, and enhances cognitive abilities. Furthermore, 480 nm blue light exposure reduces fluctuations in NSCs stemness gene expression induced by SD, potentially through its effect on enhancing the amplitude of suprachiasmatic nucleus (SCN) circadian oscillations. These findings may provide novel strategy for alleviating rotating circadian rhythm-related anxiety and learning and cognitive obstruction.

Osteoarthritis (OA) is a growing health concern worldwide. This disease is a major concern in human and veterinary patients, especially in growing and geriatric individuals. The poor regenerative capacity of damaged cartilage affects the healing process. Currently, no effective treatment strategy exists that provides a complete cure. Despite several traditional and pharmacological treatments, none of them resulted in the repair and regeneration of cartilage tissue. Regenerative therapy has gained increasing attention in the treatment of OA as it is directly involved in the regenerative process of damaged cartilage. The mesenchymal stem cells (MSCs) have therapeutic potential in treating OA resulting from their paracrine action on host cells, mediated via cytokines, exosomes, growth factors, and extracellular matrix molecules. Even though no significant side effects are documented, cell-based therapeutics could still present some risks. Exosomes, on the other hand, act primarily by channelizing the resident cells to restore the damaged cartilage and thus play an essential role in the treatment of OA. This review explores the regenerative efficacy of exosomes in managing OA in veterinary patients, elucidating their mechanisms of action and therapeutic potential. Recognizing the importance of comprehending exosomes and their mechanisms is crucial for developing safe and effective cell-free therapeutics for OA. This paper aims to enhance our understanding of cell-free regenerative strategies, paving the way for the development of innovative treatments for OA in veterinary medicine.

Ruminants are of significant economic importance, and their unique digestive system features the rumen as a vital organ. The rumen is lined by stratified squamous epithelium, plays a crucial role in absorbing volatile fatty acids (VFAs) generated through microbial fermentation, thereby meeting the daily energy requirements of these animals. The maintenance of the rumen epithelium is a matter of concern. Here, we present compelling evidence that the hippo pathway effector yes-associated protein 1 (YAP) serves as a key regulator in maintaining rumen epithelial cells (RECs). Our findings indicate that rumen epithelial basal cells spontaneously undergo expansion and differentiation, ultimately forming organoids, and that the hippo signaling pathway is involved in regulating this process. Specifically, we demonstrate that YAP is indispensable for the initial specification and long-term maintenance of organoids. Activation of YAP promotes the growth and formation of these organoids, whereas inhibiting YAP hinders this developmental process. YAP activation exerts its effects by enhancing basal cells proliferation while simultaneously inhibiting differentiation. Conversely, YAP inhibition reduces the proliferation of basal cells. Notably, YAP activation promotes dedifferentiation of differentiated organoids. Moreover, YAP activation fosters intercellular tight junctions and strengthens cell-extracellular matrix interactions. In contrast, YAP inhibition reverses these features and leads to the disintegration of the organoids. Collectively, our data reveal the regulatory role of YAP in the rumen epithelium, which will help deepen the understanding of rumen development.