Cell Transplantation最新文献

The effective application of allogeneic mesenchymal stem cells (MSCs) has the potential to enhance cartilage regeneration. This study aimed to evaluate the therapeutic efficacy of intra-articular (IA) injections of small umbilical cord-derived fast proliferating cells (smumf cells) combined with magnesium (Mg²⁺) in a rat model of full-thickness cartilage defects (FTDs). Adhesion of smumf cells was assessed on type I collagen-coated surfaces in vitro, in an uncontained ex vivo model, and via cell tracking in a rat FTD model. Therapeutic efficacy was evaluated using histological analyses of macroscopic and microscopic in vivo (at 4 and 8 weeks, n = 6). Mg²⁺ improved the adhesion of smumf cells by up to 1.89-fold in the ex vivo model, and by 2.80-fold in cell tracking. A single injection of smumf cells alone improved histological scores by 2.33-fold at 4 weeks, whereas the combination with Mg²⁺ resulted in further improvements in both macroscopic (1.30-fold) and microscopic (1.26-fold) scores at 8 weeks. Moreover, the smumf cells + Mg²⁺ group showed significant increases in tissue thickness (1.40-fold), safranin O-positive area (2.88-fold), and type II collagen synthesis (1.22-fold) in rat model. This study demonstrates that a single IA injection of smumf cells combined with Mg² enhances cell homing and functional adhesion at the defect site, thereby promoting superior cartilage regeneration compared with smumf cells alone.

Knee osteoarthritis (OA) causes pain and disability, and autologous adipose-derived stem cell (ASC) therapy has emerged as a regenerative treatment option. This retrospective cohort study compared short-term outcomes of intra-articular ASC injections between patients with moderate (Kellgren-Lawrence [KL] 2/3) and severe (KL 4) OA. Among 242 treated patients, 98 in each group were analyzed after propensity score matching for age, sex, and body mass index. Pain (VAS) and Knee Injury and Osteoarthritis Outcome Score (KOOS) subscales were evaluated at baseline and 1, 3, and 6 months. Both groups showed significant improvements in pain and function, with KL 2/3 patients exhibiting greater gains in KOOS Total, Activities of Daily Living, Sports/Recreation, Quality of Life, and VAS pain compared with KL 4. KOOS pain and symptoms improved similarly in both groups. Analgesic effects increased over time, and no serious adverse events were observed. Mild transient swelling or discomfort occurred in about 5% to 6% of cases. ASC injections provided meaningful symptom relief and functional improvement, particularly in moderate OA, suggesting that preserved joint structure benefits therapeutic efficacy. In advanced OA, benefits were present but attenuated, indicating limited regenerative potential in end-stage disease.

Extracellular vesicles (Evs) act as a natural intercellular message transmitter, Evs can carry proteins, ribonucleic acid (RNA) and other bioactive substances, and have rich biological regulatory functions. Because of its low immunogenicity and high biocompatibility, it has become a popular research object in drug delivery. These remarkable properties also create new opportunities for modern therapy. However, due to the complex preparation process, there are challenges in terms of targeting accuracy, load release controllability, and pharmacokinetic optimization, and many problems may be encountered in reality. Based on real-life biomedical experiments, this paper summarizes the methods and types of Evs loading drugs, membrane modification methods, and the use of biological materials to improve the release efficiency, so as to provide reference for future research on engineered Evs.

Although islet transplantation is effective in reducing severe hypoglycemia events and controlling blood glucose in patients with type 1 diabetes, maintaining islet graft function long-term is a significant challenge. Islets from multiple donors are often needed to achieve insulin independence, and even then, islet function can decline over time when metabolic demand exceeds islet mass/insulin secretory capacity. We previously developed a method that calculated the islet graft function index (GFI) and a patient's predicted insulin requirement (PIR) using mathematical nonlinear regression. Both PIR and GFI could be used by physicians as tools to monitor islet graft function and to guide supplementing the patient with exogenous insulin to prevent beta-cell exhaustion. This study investigates the factors relating to the islet preparation process, as well as donor and recipient characteristics, and assessed their associations with PIR and GFI after transplantation. The goal is to determine the most relevant factors that influence islet graft function after transplantation. We examined the effects of donor and recipient characteristics, and islet processing factors on posttransplanted PIR and GFI. The PIR and GFI at 3 months were calculated using patients' baseline insulin intake, posttransplant 2-h postprandial blood glucose, and glucagon-stimulated C-peptide. Thirteen transplants that resulted in progressive decline in patients' weekly averaged insulin intake over the initial weeks after transplant (assuming constant glucose level) with available 3-month PIR and GFI data were chosen for the investigation. Univariate analyses were performed to assess the effects of donor and recipient characteristics and islet processing factors on islet graft function as reflected by PIR and GFI. The PIR and GFI were treated as continuous response variables in separate linear regression models. Shorter digestion time of isolated donor islets were associated with lower PIR (P = 0.014) and a higher GFI (P = 0.027) after transplantation. Islet injury related to digestion enzyme exposure influenced islet function as estimated using PIR and GFI post-transplantation.

Herein, we characterized the percentage of tacrolimus to the combined sirolimus and tacrolimus trough levels (tacrolimus %) observed during islet transplant-associated immune suppression therapy with post-transplant skin cancer. Although trough levels of tacrolimus and sirolimus were not different (P = 0.79, 0.73, respectively), high tacrolimus % resulted in a 1.32-fold increase in skin cancer odds when adjusting for age, sex, body mass index (BMI), and use of mycopheonlate mofetil (MMF; p = 0.039). Skin cancer patients were likely to have been older but not differ significantly (mean difference 12 years, P = 0.056), but age was significantly associated with a 1.22-fold increase in adjusted skin cancer odds (P = 0.046). BMI was inversely associated with skin cancer, with an adjusted odds ratio (OR) of 0.40 (P = 0.022). High tacrolimus % (>35) resulted in a 4.6-fold increase in skin cancer frequency, whereas sirolimus above 75% of the combined therapy led to a 5.2-fold increase in islet graft dysfunction (IGD) events/year. By calculating the maximum safe exposure (MSE) to tacrolimus % according to patient age and BMI, we found that cumulative months spent above MSE was predictive of skin cancer (1.20-fold increase, P = 0.003). Individuals exceeding the MSE for 1 year were 9.2 times more likely to develop skin cancer (P = 0.008). Results suggest that strategies targeting immunosuppression ratios based on age and BMI may minimize cancer risk while improving graft survival and function.

Peripheral nerve injuries involving nerve defects remain challenging to treat. Although autologous nerve grafting is considered the gold standard, it has notable limitations, including donor site morbidity. To address this, we developed a scaffold-free Bio 3D conduit composed of human umbilical cord-derived mesenchymal stromal cells (UC-MSCs) using bioprinting technology. In this study, we evaluated its efficacy and safety in a canine ulnar nerve defect model. At 10 weeks postoperatively, the Bio 3D group showed better motor and sensory recovery compared with the allograft group, as demonstrated by the pinprick test, electrophysiological studies, and hypothenar muscle wet weight (0.978 ± 0.100 vs. 0.637 ± 0.151, n = 3). Morphometric analysis revealed greater axonal regeneration, including larger myelinated axon diameters (4.27 ± 0.342 µm vs. 3.69 ± 0.161 µm, n = 3) and thicker myelin sheaths (0.621 ± 0.088 µm vs. 0.497 ± 0.021 µm, n = 3). Immunostaining showed that the number of transplanted UC-MSCs diminished over time, likely after exerting their therapeutic effects. No adverse events, systemic abnormalities, or distant human cell migration was observed. These findings suggest that UC-MSC-derived Bio 3D conduits are a promising alternative for peripheral nerve regeneration, especially for patients wishing to avoid donor nerve harvesting.

The impact of early tacrolimus (TAC) blood levels on acute graft-versus-host disease (aGVHD) and transplant outcomes in adults undergoing haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with posttransplant cyclophosphamide (PTCy) is incompletely investigated. We retrospectively analyzed 161 T-cell-replete haplo-HSCT with PTCy, TAC, and mycophenolate-mofetil. TAC trough levels from weeks 1-2 (w1/2) and weeks 3-4 (w3/4) posttransplant were categorized as "Low" or "High" using a threshold of 10 ng/ml. Outcomes assessed included grade III-IV acute graft-versus-host-disease (aGVHD), nonrelapse mortality (NRM), relapse, and overall survival (OS). Multivariate analyses controlled for relevant patient and transplant factors. Higher w1/2 TAC (≥10 ng/ml) in weeks 1-2 had no association with aGVHD III/IV (35% vs. 35%, P = 0.71). Higher TAC levels during w3/4 were associated with a trend toward decreased aGVHD III-IV incidence (8% vs. 20%; P = 0.09). Multivariate analysis confirmed w3/4 TAC levels as protective against aGVHD III/IV (sub-Hazard Ratio [sHR] = 0.83, 95% CI: 0.70-0.98, P = 0.03) and NRM (sHR = 0.82, 95% CI: 0.71-0.95, P = 0.01), while w1/2 TAC levels had no significant impact on the above outcomes. TAC levels did not significantly impact OS or relapse. We conclude that following PTCy-based haplo-HSCT, higher TAC levels during weeks 3-4 may decrease aGVHD and NRM.

Cell-based therapies, particularly transplanted human oligodendrocyte progenitor cells (OPCs), are being explored for neuroprotection and remyelination in demyelinating diseases of the central nervous system (CNS). In this study, we investigated the potential of OPC transplantation into the optic nerve of dark agouti (DA) rats with experimental autoimmune encephalomyelitis (EAE). Human OPCs were transplanted 30 days after EAE induction in one optic nerve, while the contralateral nerve was injected with a vehicle. FTY720 (fingolimod) was administered starting from day 25 post-EAE to prevent graft rejection. Rats were monitored clinically and electrophysiologically using visually evoked potentials (VEPs) for up to 90 days post-transplant. Histological analysis of OPC viability, myelin, and axonal integrity was performed on days 30, 60, and 90 post-transplant. At days 30 and 60, sparse OPCs were detected in the injected optic nerve. However, no live cells were detected on day 90. There were no significant differences in myelin or axonal integrity between the OPC- and vehicle-injected nerves. The VEP traces were severely distorted throughout the 90-day follow-up. This approach did not show long-term viability following direct injection of OPCs in the optic nerve of EAE rats. Challenges related to graft rejection and cell transplantation are discussed, with implications for future research in cell-based therapies.

Allogeneic skin transplantation faces significant immunological challenges due to immune rejection, primarily mediated by dendritic cells (DCs). Adipose-derived stem cells (ADSCs) possess immunomodulatory effects; however, the underlying molecular mechanisms in regulating DC function remain unclear. This study aimed to investigate the regulatory effects of ADSCs and tumor necrosis factor-α-stimulated gene 6 (TSG-6) secreted by ADSCs on DC in the murine allogeneic skin transplantation. Following transplantation, recipients received ADSCs, TSG-6 knockdown ADSCs (ADSCs-shTSG-6), or control treatments. Immune cell infiltration and cytokine expression were analyzed by flow cytometry and immunohistochemistry. Transwell assays were used to assess the effect of TSG-6 on DCs migration. TSG-6-related gene expression profiles were explored using transcriptomic analysis and validated by RT-qPCR. ADSC treatment significantly reduced the migration of DCs to the recipient than the ADSCs-shTSG-6 treatment, while reducing the levels of macrophages, lymphocytes, and pro-inflammatory cytokines. ADSC-derived TSG-6 inhibited DCs migration, an effect diminished upon TSG-6 knockdown and restored by TSG-6 supplementation. Transcriptomic analysis identified a panel of immune-related genes (ADM, GHRH, SELENBP1, NDRG1) regulated by TSG-6. These findings indicate that ADSCs enhance graft tolerance by inhibiting DCs migration via TSG-6 secretion, highlighting TSG-6 as a promising therapeutic target for preventing transplant rejection.

Glucose-stimulated insulin secretion (GSIS) testing of isolated islets of Langerhans is crucial for assessing β-cell function, yet protocol variability complicates result interpretation. This study investigated insulin secretion heterogeneity across 576 donors and examined the influence of donor characteristics on secretory responses. We compared static incubation (n = 408) and dynamic perifusion (n = 168) techniques using standardized glucose stimulation protocols (3 vs 15 mM). While both methods showed comparable stimulation indices (r² = 0.652), dynamic perifusion uniquely captured temporal secretion patterns and revealed greater dynamic range in insulin responses. Notably, dynamic perifusion, with insulin content normalization, revealed a 22-fold variation in stimulation index across donors. Body mass index (BMI) and HbA1c significantly influenced basal insulin secretion, particularly in donors with glucose intolerance and type 2 diabetes (T2D) (HbA1c ≥ 6.5%). Cluster analysis identified two distinct groups based on age, BMI/body surface area (BSA), and HbA1c, which strongly predicted insulin secretion patterns, whereas donor sex had no measurable impact. This large-scale study demonstrates the superiority of standardized perifusion over static incubation for resolving islet glucose responses. By capturing dynamic secretion profiles, perifusion reveals substantial donor heterogeneity, primarily driven by BMI and HbA1c through their effects on basal insulin secretion.