Stem Cells Translational Medicine最新文献

Background: The transplantation of autologous muscle precursor cells (MPCs) is effective in the regeneration of muscle in multiple pathologies. This phase I clinical trial sought to use MPCs to treat stress urinary incontinence (UI).

Methods: Female patients with either stress urinary incontinence (SUI) or congenitally acquired UI had thigh muscle biopsies prior to MPC expansion and processing. The MPCs were injected directly into the bladder neck. Symptoms were measured using pad weight tests (1-h and 3-day), baseline questionnaires (Urogenital Distress Inventory [UDI-6], Incontinence Impact Questionnaire [IIQ-7]), and self-reported accident frequencies.

Results: Ten women aged 16-75 were included. For the 8 SUI subjects, there was a reduction in pad weight between pre- and post-treatment for the 1-h (P < .0001) and 3-day (P = .0076) pad tests after adjusting for age, gravida, and body mass index. The reduction was observed by the 6-week post-treatment visit and remained relatively constant thereafter. There was no evidence of a difference among the 4 post-treatment pad weights for either the 1-h (P > .05) or the 3-day (P > .05) pad tests. Similarly, there was evidence of a reduction from pre- to post-treatment in UDI-6 (P = .0034), IIQ-7 (P = .0455), and the number of self-reported accidents (P = .0656). There was no evidence of regression during the post-treatment visits for UDI-6 (P > .5), IIQ-7 (P > .25), and the number of self-reported accidents (P > .25). The 2 subjects with congenital incontinence did not improve (P > .05).

Conclusions: Autologous thigh muscle-derived MPC injection into the bladder neck is a safe and well-tolerated treatment for acquired stress UI in adult women.

The regulation of the hair cycle is orchestrated by a complex network of signaling pathways, and substantial evidence from extensive research indicates that exosomal miRNAs may play a pivotal role in this process. In this study, we present compelling evidence that exosomes derived from human umbilical cord mesenchymal stem cells (hUC-MSCs), pretreated with the Wnt pathway agonist lithium chloride (LiCl), significantly enhance hair regeneration. High-throughput sequencing was utilized to identify differentially expressed miRNAs in exosomes from both LiCl-pre-treated and untreated groups, thereby elucidating potential mechanisms underlying this phenomenon. Specifically, miR-146a-5p was found to activate the Wnt signaling pathway, thereby promoting the proliferation and migration of primary dermal papilla cells in mice. The downstream target genes of miR-146a-5p, including SFRP1, SMAD2, SMAD4, and EGFR, were predicted using bioinformatics tools and subsequently validated through experimental validation. An animal model overexpressing miR-146a-5p was constructed, demonstrating that miR-146a-5p targets SFRP1 to promote hair regeneration in mice via activation of the Wnt signaling pathway.

Chronic compressive cervical spinal cord injury (cCSCI), a debilitating condition, lacks effective treatment options. Addressing this gap, our study introduces a novel rat model of cCSCI developed through spinal cord compression via synthetic polyether sheet implantation, closely mimicking human pathology. We evaluated the model's fidelity utilizing a comprehensive series of behavioral, electrophysiological, and histological assessments. Our research also explored the therapeutic potential of oligodendrogenic neural progenitor cells (oNPCs) derived from induced pluripotent stem cells. Transplanted oNPCs successfully integrated into the host spinal cord, differentiated into neurons, astrocytes, and oligodendrocytes, and demonstrated a remarkable capacity for enhancing neuroplasticity. Electrophysiological analyses revealed significant improvements in motor evoked potentials and a rectification of the excitability imbalance posttransplantation, indicating substantial recovery of motor circuits. Histological findings complemented these results, showing enhanced remyelination and a reduction in excitatory transmitter expression in the residual gray matter. Functionally, the transplantation of oNPCs led to marked improvements in grip strength, locomotor abilities, and sensory functions, surpassing those seen with standard treatments. This study not only provides a novel and reliable rat model of cCSCI for further research but also highlights the potential of oNPCs as a transformative approach for spinal cord injury therapy, suggesting their significant role in neural regeneration and repair.

Neonatal disorders affecting different organs are highly multifactorial and involve a complex interplay among prematurity, inflammation, oxidative stress, tissue injury, immune dysregulation, and impaired regeneration. Conditions such as hypoxic-ischemic encephalopathy, intraventricular hemorrhage, neonatal stroke, bronchopulmonary dysplasia, and necrotizing enterocolitis often result from or cause multi-organ dysfunction. This multifaceted nature presents a substantial therapeutic challenge, as current treatment plans are largely supportive and are limited to addressing the underlying immaturity and injury. Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) have emerged as promising cell-free therapeutics owing to their ability to modulate inflammation, promote repair, and support organ maturation. By delivering a rich secretome of proteins, lipids, and regulatory RNAs, MSC-EVs retain the regenerative benefits of mesenchymal stromal cells while offering improved safety and storage. This review provides a comprehensive overview of MSC-EV therapy for neonatal disorders, focusing on the mechanisms of action, preclinical evidence, and future perspectives on clinical translation. By integrating the currently available study findings, this review highlights the potential of MSC-EVs as a multifaceted therapy for preterm infants, capable of addressing both tissue injury and developmental immaturity.

Immune system disorders underlie numerous chronic inflammatory diseases. Functional status and normal apoptosis of neutrophils are of great significance in the regulation and outcome of inflammation. Excessive activation and delayed apoptosis of neutrophils can lead to additional tissue damage, which may be an important cause of delayed disease recovery. Stem cells have immunomodulatory effects, but transplanted stem cells are prone to apoptosis in the hypoxic-inflammatory microenvironment. However, the capacity of stem cell-derived apoptotic bodies (ApoBDs) to regulate neutrophil functions, along with the specific components and mechanisms involved, is still unclear. Our study revealed that ApoBDs stemming from hypoxia-induced apoptosis in bone marrow mesenchymal stem cells reversed Lipopolysaccharide (LPS)-induced delayed neutrophil apoptosis, without notable effects on neutrophil apoptosis under physiological conditions. This functional shift was attributed to the phagocytosis of miR-125b-5p within ApoBDs by neutrophils, which inhibited the activation of the PI3K-AKT signaling pathway. In a mouse skin wound healing model, ApoBDs and the miR-125b-5p they contain also promoted neutrophils apoptosis around the wound and early wound closure. In summary, we demonstrated that hypoxia-induced apoptosis of bone marrow mesenchymal stem cells produced ApoBDs by transferring miR-125b-5p to neutrophils to reduce the expression of PI3 Kinase p110α and inhibit the activation of the PI3K-AKT signaling pathway, thereby reversing the delay of neutrophil apoptosis induced by LPS, which may be a novel option for the treatment of diseases associated with abnormalities in neutrophil apoptosis.

Purpose: In biliary atresia (BA), it has been demonstrated that biliary epithelial-mesenchymal transition (EMT) of reactive ductular cells is associated with liver fibrosis. This study aimed to develop an ex vivo biliary EMT model of liver ductal organoids for exploring the involvement of biliary EMT in fibrogenesis and to investigate whether human amniotic fluid stem cells (hAFSCs) can mitigate the biliary EMT process.

Methods: Liver ductal organoids were generated from the intrahepatic bile duct of healthy neonatal mice. Biliary EMT was induced in organoids by the administration of transforming growth factor beta-1 (TGF-β1) in culture medium. hAFSCs were co-cultured with organoids during biliary EMT induction. Expression of biliary epithelial cells, mesenchymal cells, myofibroblast, collagen I, and genes related to the Wnt signaling pathway were evaluated.

Results: Following administration of TGF-β1, we observed an increased expression of mesenchymal cell markers N-cadherin and Vimentin, as well as myofibroblast marker alpha-smooth muscle actin (α-SMA) in liver ductal organoids which were associated with increased expression of collagen 1. Administration of hAFSCs to organoids significantly attenuated TGF-β1-induced biliary EMT and collagen production. In addition, Wnt signaling was upregulated in biliary EMT, while hAFSCs downregulated the Wnt signaling resulting in decreased expression of myofibroblast and collagen in organoids.

Conclusion: TGF-β1 is a potent cytokine that induces biliary EMT. hAFSCs significantly mitigated TGF-β1-induced biliary EMT in liver ductal organoids. The beneficial effect of hAFSCs administration is associated with the downregulation of the Wnt signaling pathway. This study indicates that hAFSCs can prevent the progression of liver fibrosis in BA.

Chronic limb threatening ischemia (CLTI) is the most severe form of peripheral vascular disease which can lead to amputation with a high associated mortality rate. Endothelial colony forming cells (ECFCs) show potential as a cell therapy to revascularize the limbs of individuals with CLTI. However, autologous ECFCs from patient peripheral blood (PB) have been reported to have a dysfunctional phenotype. We investigated this disease phenotype in individuals with CLTI, with and without diabetes mellitus (DM), to determine ECFC suitability as an autologous cell therapy. PB-ECFCs were isolated from age-matched controls, individuals with DM, and individuals with CLTI, with and without DM. The frequency of isolating ECFCs from this donor cohort was calculated. Furthermore, in vitro characterization assays were performed (growth kinetics, angiogenic properties, and reactive oxygen species [ROS] levels) and compared between donor groups. We report a significantly increased frequency of ECFCs from individuals with CLTI, with and without DM. Furthermore, our results demonstrate no significant disease related effect on the in vitro functional properties of ECFCs between cohorts. However, there is a significantly higher in vitro angiogenic capacity in individuals with DM vs age-matched controls. Our results demonstrate that ECFCs can be isolated in individuals with CLTI, with and without DM, and that ECFC functionality is similar between cohorts. Therefore, if the ∼70% isolation efficiency from both CLTI cohorts is overcome, then autologous PB-ECFCs may be a suitable therapeutic for CLTI. Further analysis is needed to determine the critical quality attributes of ECFCs from this patient population.

Background: Stem cell research has rapidly advanced during the past decades, but the translation into approved clinical products is still lagging behind. Multiple barriers to effective clinical translation exist. We hypothesize that an ineffective use of the existing wealth of data from both product development and clinical trials is a crucial barrier that hampers effective clinical implementation of stem cell therapies.

Methods and results: Here, we summarize the contribution of systems biology (SysBio) and artificial intelligence (AI) in stem cell research and therapy development, to better understand and overcome these barriers to effective clinical translation. Advancements in cell product profiling technology, clinical trial design, and adjunct clinical monitoring, offer new opportunities for a more integrated understanding of both, product and patient performance. Synergy of SysBioAI analysis is boosting a more rapid, integrated, and informative analysis of large‑scale multi‑omics data sets of patient and clinical trial outcomes, thus enabling the "Iterative Circle of Refined Clinical Translation". This SysBioAI‑supported concept can assist more effective development and clinical use of stem cell therapeutics through iterative adaptation cycles. This includes product‑ and patient‑centered clinical safety and efficacy/potency evaluation through paired identification of suitable biomarkers of clinical response.

Conclusion: Integrated SysBioAI-use is a powerful tool to optimize the design and outcomes of clinical trials by identifying patient-specific responses, contributing to enhanced treatment safety and efficacy, and to spur new patient-centric and adaptable next-generation deep-medicine approaches.

Background: Joint bone destruction in rheumatoid arthritis (RA) leads to poor prognosis, with current treatments mainly targeting inflammation and limited focus on bone damage. Mesenchymal stem cells (MSCs) offer anti-inflammatory and bone repair properties, but their clinical application is hindered by cellular heterogeneity. Induced pluripotent stem cell-derived mesenchymal stem cells (iMSCs) present a promising alternative due to their lower heterogeneity and replicative senescence, although their potential in RA treatment remains underexplored.

Methods: iMSCs were injected intraarticularly in a collagen-induced arthritis (CIA) model. Treatment outcomes, including plantar swelling, joint score, histological and immunohistochemical staining, microCT imaging, and bone loss, were assessed. Single-cell RNA sequencing was employed to study iMSCs' effects on synovial macrophage subsets.

Results: In vivo, iMSCs significantly reduced systemic inflammation and joint bone damage. Analysis of macrophage subpopulations revealed that iMSCs shifted macrophages from a pro-inflammatory CD86hiIL1βhi cluster to an anti-inflammatory CD86hiIL1βlo cluster, leading to reduced inflammation and bone resorption.

Conclusions: iMSCs effectively alleviate inflammation and bone damage in CIA by modulating macrophage phenotypes, demonstrating potential for RA therapy.

Hematopoietic stem cells (HSCs) reconstitute blood cells throughout life. DNA-level correction of HSCs allows for a one-time cure of genetic diseases, including sickle cell disease (SCD). Sickle cell disease is one of the most common single-gene disorders; therefore, SCD is a prime candidate for gene therapy. Several drug therapies are available for SCD, including hydroxyurea, which is the first-line choice despite requiring lifelong administration. Allogeneic HSC transplantation is a one-time, curative treatment for SCD with limited availability of histocompatible donors. Therefore, autologous HSC gene therapy was developed using patients' own HSCs with lentiviral gene addition/silencing and clustered regularly interspaced short palindromic repeats gene editing, making gene therapy applicable to most patients. However, the established method of HSC gene therapy requires costly and complex ex vivo HSC culture. Therefore, in vivo HSC gene therapy is being developed to treat SCD, envisioning a single-injection HSC-targeted gene delivery system. This review discusses various therapeutic methods to treat SCD, the development of HSC gene therapy, and clinical gene therapy trials in SCD, ranging from FDA-approved to novel in vivo gene therapy.