Stem Cells International最新文献

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.

Aging, linked to reduced tendon healing and higher injury susceptibility, is associated to the high incidence of rotator cuff (RC) tears in the elderly. Even after RC repair, disordered neofibrovascular scar tissue often occurs, lowering mechanical strength, and tendon-derived cell (TDC) senescence has been suggested as one of the causes. Age reduces the efficacy of mesenchymal stem cell (MSC) therapy for tendon regeneration. However, certain biomaterial exposure may increase MSC differentiation and paracrine effects. We aimed to develop and evaluate an optimal tenon-MSC complex (TSC) for tendon regeneration and investigate its efficacy and antisenescence mechanisms in aged and degenerated TDCs. We proposed a novel method to isolate a maximum quantity of tenon with col6-rich pericellular matrix (PCM) per gram of tendon, utilizing 2% collagenase. In a fibrin 3D gel culture system, rejuvenated METn (TSC) had higher tenogenic marker expression, collagen fiber quantity, and quality than MSC-only or METc (TDC-MSC complex). METn could repair DNA damage and improve cellular metabolism in senescent TDCs by releasing antisenescence factors. TDCs, which overcomes senescence by the METn_CM treatment, also produced a higher quality tendon matrix. In conclusion, this study demonstrates that rejuvenated and functional TSC significantly enhances tendon regeneration by countering senescence in aged and degenerated TDCs, offering a safe approach to enhance the therapeutic potential of autologous senescent MSCs from the elderly.

Background: The periosteum plays an indispensable role in bone repair, and promoting osteogenic differentiation of periosteum-derived stem cells (PDSCs) is one of the most effective strategies for enhancing spontaneous bone regeneration in maxillofacial bone defects. Methods: We established a rat model of mandibular defects with preserved periosteum to explore its bone regeneration capacity and the potential mechanisms of PDSC activation and osteogenic differentiation. Results: Significant bone regeneration was observed in rats with preserved periosteum after mandibular defects. To explore the underlying mechanisms, PDSCs were isolated from the periosteum of rat mandibles, and the stem cell markers CD90 and CD44 was highly expressed in these PDSCs. Further, RNA-seq, RT-qPCR, and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses revealed significantly reduced expression of the Dot1l gene, and the Notch pathway was significantly enriched in the PDSCs of the model group. Osteogenic assays demonstrated that the overexpression of Dot1l significantly inhibited the alkaline phosphatase (ALP) activity, calcium deposition, and the expression of osteogenic-related genes (such as RUNX2, OSX, ALP, and OCN) in PDSCs. Additionally, Dot1l significantly affects the Notch signaling pathway in the Gene Ontology (GO) pathways, and significantly downregulates the expression of Chac1 within it. Further, Dot1l inhibited ALP activity, calcium deposition, and the expression of osteogenic-related genes in PDSCs by downregulating Chac1 expression. Conclusions: Our study suggests that mandibular defects can induce the activation of PDSCs and inhibit the expression of Dot1l, potentially affecting the Notch signaling pathway. Targeting the Dot1l/Chac1 pathway to regulate the osteogenic differentiation of PDSCs lays a solid foundation for periosteum-based maxillofacial bone regeneration.

Mesenchymal stem cells (MSCs) exhibit great promise for treatment applications because of their immunosuppressive properties. The aryl hydrocarbon receptor (AHR), which is a transcription factor that is activated via ligand, has a pivotal role in regulating the immune system and is involved in a range of immune-related disorders. However, hyperglycemia, the defining biochemical hallmark of diabetes, creates a chronically pro-inflammatory microenvironment that impairs the immunoregulatory effects of MSCs. In this study, we explored the potential of kynurenic acid (KYNA) and quercetin, two naturally derived compounds, to modulate the immune response of MSCs through the regulation of AHR signaling under hyperglycemic conditions. We assessed the immunophenotyping and differentiation capacity of cultured human umbilical cord mesenchymal stem cells (hUC-MSCs) in a high-glucose medium and quantified the mRNA expression rate of AHR, CYP1A1, CYP1B1, and IL-6 using real time PCR. Our study is the first to reveal that KYNA and quercetin enhance mRNA expression levels of AHR and CYP1B1, while reducing IL-6 expression in hUC-MSCs, suggesting their potential as immunomodulators. These findings highlight the compounds' promise as drug candidates for immune-mediated diseases through stem cell therapy, particularly due to their modulation of AHR.

Mesenchymal stromal cells (MSCs) are recognized for their differentiation and immune regulation capabilities, which enhance their potential for treating various diseases. MSCs can be sourced from diverse tissues, with peripheral blood (PB) serving as a viable alternative to bone marrow. We now present an alternative strategy that eliminates the need for preadministering growth factors, utilizing density gradient methods, and culturing target cells in medium supplemented with autologous serum. PB was collected through venipuncture and then coincubated with glycerin. After incubation, a thin layer of cells above the red blood cells (RBCs) was isolated, showing an increased population of CD34^-CD45^- cells compared to PB mononuclear cell (PBMC) isolation using Ficoll gradient. After culture, adherent spindle-shaped cells were identified and collected to assess MSC surface markers, demonstrating their differentiation potential into adipocytes, osteocytes, and chondrocytes, thus, fulfilling the criteria for MSCs. The population doubling time (PDT) of isolated PB-MSCs was approximately 30-40 h in early passages. These PB-MSCs also exhibited immunomodulatory functions and are capable of suppressing T cell activation. We believe this protocol supports PB as a convenient alternative source for MSC isolation and offers new strategies for acquiring and maintaining PB-MSCs.

Background: In recent years, liver regeneration therapy using mesenchymal stem cells (MSC) has been investigated as an alternative therapy for end-stage liver diseases. Among these MSCs, multilineage-differentiating stress enduring (Muse) cells are reported to be effective in mouse models. The present study investigated the safety and effectiveness of Muse cell transplantation in large animal models of hepatic fibrosis. Methods: Muse cells and MSC were prepared from bone marrow cells of male mini pigs (Göttingen strain). Recipients mini pigs (female Göttingen strain) were repeatedly administered with carbon tetrachloride (CCl₄) intraperitoneally for 12 weeks to induce liver fibrosis. Thereafter, either Muse cells or MSCs were transplanted intravenously. After the cell transplantation, laboratory tests, vital signs, and liver histology were evaluated (Muse cell group (n = 6), MSC group (n = 6), and vehicle group (n = 7)). Results: Liver fibrogenesis was successfully induced after 12 weeks of CCl₄ administration. Engraftment of transplanted cells and differentiation into hepatocytes were confirmed in recipients' liver. In Muse cell group, significant increase of serum albumin (Alb) level was observed at 4 weeks compared to those of control groups (p  < 0.05). Hepatic proliferating cell nuclear antigen (PCNA) positive cells were significantly increased in the Muse cell group (p  < 0.05). Hepatic fibrogenesis at 12 weeks after transplantation were significantly improved in Muse cell group (p  < 0.05). Alpha-smooth muscle actin (α-SMA) immunostaining revealed significant decrease in liver from Muse cell transplanted recipients. No serious adverse effects were observed. Conclusions: Muse cell transplantation was safe and effective in large animal models of hepatic fibrosis. The positive effects were observed in namely 4 weeks after transplantation. Since biochemical as well as histological improvements were demonstrated, future studies including establishing ideal administration protocol seem to be feasible as a preclinical study.