Stem Cells Translational Medicine最新文献

Pulmonary fibrosis is a kind of fibrotic interstitial pneumonia with poor prognosis. Aging, environmental pollution, and coronavirus disease 2019 are considered as independent risk factors for pulmonary fibrogenesis. Consequently, the morbidity and mortality striking continues to rise in recent years. However, the clinical therapeutic efficacy is very limited and unsatisfactory. So it is necessary to develop a new effective therapeutic approach for pulmonary fibrosis. Human umbilical cord mesenchymal stem cells (hucMSCs) are considered as a promising treatment for various diseases because of their multiple differentiation and immunomodulatory function. The key bottleneck in the clinical application of hucMSCs therapy is the high-quality and large-scale production. This study used FloTrix miniSpin bioreactor, a three-dimensional (3D) cell culture system, for large-scale expansion of hucMSCs in vitro, and proved 3D cultured hucMSCs inhibited the differentiation of fibroblasts into myofibroblasts and myofibroblasts proliferation and migration, leading to slow down the development of pulmonary fibrosis. Further mechanistic studies clarified that hucMSCs reduced the amount of binding between circELP2 and miR-630, resulting in blocking YAP/TAZ translocation from cytoplasm to nucleus. This condition inhibited mitochondrial fusion and promoted mitochondrial fission, and ultimately improved fusion/fission balance and cellular homeostasis. To sum up, this work clarified the anti-fibrosis and mechanism of hucMSCs cultured from the 3D FloTrix miniSpin bioreactor. We hope to provide new ideas and new methods for the clinical transformation and industrialization of hucMSCs therapy.

Cellular therapies rely on highly specialized supply chains that often depend on single source providers. Public cord blood banks (CBB) manufacturing the first cell therapy to be highly regulated by the FDA and related international agencies are a prime example of being subject to this phenomenon. In addition to banking unrelated donor cord blood units for transplantation, CBBs also source and characterize starting materials for supply to allogeneic cell therapy developers that often employ customized technologies offered by just a small number of manufacturers. As such, these supply chains are especially sensitive to even minor changes which often result in potential major impacts. Regulations can shape supply chain efficiencies, both directly via the definition of restricted technology and process requirements and indirectly by steering strategic business decisions of critical supply or service providers. We present 3 current supply chain issues with different root causes that are swaying efficiencies in cord blood banking and beyond. Specifically, the shortage of Hespan, a common supplement used in cord blood processing, the decision by the provider to stop supporting medical device marking of the Sepax system broadly used in cord blood banking, and a new European ruling on phasing out plasticizers that are critical for providing flexibility to cord blood collection bags, are all threatening downstream supply chain issues for the biologics field. We discuss overcoming these hurdles through the prism of unified mitigation strategies, defined, and implemented by multi-factorial teams and stakeholders, to negotiate resolutions with providers and regulators alike.

Radiation therapy (RT) is a common treatment for lung cancer. Still, it can lead to irreversible loss of pulmonary function and a significant reduction in quality of life for one-third of patients. Preexisting comorbidities, such as chronic obstructive pulmonary disease (COPD), are frequent in patients with lung cancer and further increase the risk of complications. Because lung stem cells are crucial for the regeneration of lung tissue following injury, we hypothesized that airway stem cells from patients with COPD with lung cancer might contribute to increased radiation sensitivity. We used the air-liquid interface model, a three-dimensional (3D) culture system, to compare the radiation response of primary human airway stem cells from healthy and patients with COPD. We found that COPD-derived airway stem cells, compared to healthy airway stem cell cultures, exhibited disproportionate pathological mucociliary differentiation, aberrant cell cycle checkpoints, residual DNA damage, reduced survival of stem cells and self-renewal, and terminally differentiated cells post-irradiation, which could be reversed by blocking the Notch pathway using small-molecule γ-secretase inhibitors. Our findings shed light on the mechanisms underlying the increased radiation sensitivity of COPD and suggest that airway stem cells reflect part of the pathological remodeling seen in lung tissue from patients with lung cancer receiving thoracic RT.

Unproven cell-based interventions (CBIs) emerged early in the 2000s as a particularly problematic form of unproven therapy and remain a vexing policy problem to this day. These unproven interventions can harm patients both physically and financially and can complicate the process of developing a rigorous evidence base to support the translation of novel stem cell or other cell therapies. In this concise review, we examine the emergence of unproven CBIs and the various policy approaches that have been pursued or proposed to address this problem. We review the evolution of this field over the last 2 decades and explore why these policy efforts have proven challenging. We conclude by highlighting potential directions that the field could evolve and urging continued attention to both current and future forms of unproven CBIs to minimize future risks to patients and the field and to promote the development of evidence-based cell therapies.

Replicative senescence of mesenchymal stem cells (MSCs) caused by repeated cell culture undermines their potential as a cell therapy because of the reduction in their proliferation and therapeutic potential. Glutaminase-1 (GLS1) is reported to be involved in the survival of senescent cells, and inhibition of GLS1 alleviates age-related dysfunction via senescent cell removal. In the present study, we attempted to elucidate the association between MSC senescence and GLS1. We conducted in vitro and in vivo experiments to analyze the effect of GLS1 inhibition on senolysis and the therapeutic effects of MSCs. Inhibition of GLS1 in Wharton's jelly-derived MSCs (WJ-MSCs) reduced the expression of aging-related markers, such as p16, p21, and senescence-associated secretory phenotype genes, by senolysis. Replicative senescence-alleviated WJ-MSCs, which recovered after short-term treatment with bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3 (BPTES), showed increased proliferation and therapeutic effects compared to those observed with senescent WJ-MSCs. Moreover, compared to senescent WJ-MSCs, replicative senescence-alleviated WJ-MSCs inhibited apoptosis in serum-starved C2C12 cells, enhanced muscle formation, and hindered apoptosis and fibrosis in mdx mice. These results imply that GLS1 inhibition can ameliorate the therapeutic effects of senescent WJ-MSCs in patients with muscle diseases such as Duchenne muscular dystrophy. In conclusion, GLS1 is a key factor in modulating the senescence mechanism of MSCs, and regulation of GLS1 may enhance the therapeutic effects of senescent MSCs, thereby increasing the success rate of clinical trials involving MSCs.

The recently published "Minimal information for studies of extracellular vesicles - 2023 (MISEV2023)" in the Journal of Extracellular Vesicles has provided practical solutions to the numerous challenges extracellular vesicles (EVs) researchers face. These guidelines are imperative for novice and experienced researchers and promote unity within the EV community. It is strongly recommended that laboratories working with EVs make MISEV2023 an essential handbook and that researchers actively promote these guidelines during laboratory meetings, journal clubs, seminars, workshops, and conferences. A collective effort from EV researchers is crucial to steer the progress of EV science in a positive direction.

Cell therapeutic applications based on induced pluripotent stem cells (iPSCs) appear highly promising and challenging at the same time. Good manufacturing practice (GMP) regulations impose necessary yet demanding requirements for quality and consistency when manufacturing iPSCs and their differentiated progeny. Given the scarcity of accessible GMP iPSC lines, we have established a corresponding production workflow to generate the first set of compliant cell banks. Hence, these lines met a comprehensive set of release specifications and, for instance, displayed a low overall mutation load reflecting their neonatal origin, cord blood. Based on these iPSC lines, we have furthermore developed a set of GMP-compatible workflows enabling improved gene targeting at strongly enhanced efficiencies and directed differentiation into critical cell types: A new protocol for the generation of retinal pigment epithelium (RPE) features a high degree of simplicity and efficiency. Mesenchymal stromal cells (MSCs) derived from iPSCs displayed outstanding expansion capacity. A fully optimized cardiomyocyte differentiation protocol was characterized by a particularly high batch-to-batch consistency at purities above 95%. Finally, we introduce a universal immune cell induction platform that converts iPSCs into multipotent precursor cells. These hematopoietic precursors could selectively be stimulated to become macrophages, T cells, or natural killer (NK) cells. A switch in culture conditions upon NK-cell differentiation induced a several thousand-fold expansion, which opens up perspectives for upscaling this key cell type in a feeder cell-independent approach. Taken together, these cell lines and improved manipulation platforms will have broad utility in cell therapy as well as in basic research.

Background: The efficacy and safety of mesenchymal stem cells (MSCs) in the treatment of ischemic stroke (IS) remains controversial. Therefore, this study aimed to evaluate the efficacy and safety of MSCs for IS.

Methods: A literature search until May 23, 2023, was conducted using PubMed, EMBASE, the Cochrane Library, and the Web of Science to identify studies on stem cell therapy for IS. Interventional and observational clinical studies of MSCs in patients with IS were included, and the safety and efficacy were assessed. Two reviewers extracted data and assessed the quality independently. The meta-analysis was performed using RevMan5.4.

Results: Fifteen randomized controlled trials (RCTs) and 15 non-randomized trials, including 1217 patients (624 and 593 in the intervention and control arms, respectively), were analyzed. MSCs significantly improved patients' activities of daily living according to the modified Rankin scale (mean difference [MD]: -0.26; 95% confidence interval [CI]: -0.50 to -0.01; P = .04) and National Institutes of Health Stroke Scale score (MD: -1.69; 95% CI: -2.66 to -0.73; P < .001) in RCTs. MSC treatment was associated with lower mortality rates in RCTs (risk ratio: 0.44; 95% CI: 0.28-0.69; P < .001). Fever and headache were among the most reported adverse effects.

Conclusions: Based on our review, MSC transplantation improves neurological deficits and daily activities in patients with IS. In the future, prospective studies with large sample sizes are needed for stem cell studies in ischemic stroke. This meta-analysis has been registered at PROSPERO with CRD42022347156.

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) possess the intrinsic ability to differentiate into diverse cellular lineages, marking them as potent instruments in regenerative medicine. Nonetheless, the proclivity of these stem cells to generate teratomas post-transplantation presents a formidable obstacle to their therapeutic utility. In previous studies, we identified an array of cell surface proteins specifically expressed in the pluripotent state, as revealed through proteomic analysis. Here we focused on EPHA2, a protein found to be abundantly present on the surface of undifferentiated mouse ESCs and is diminished upon differentiation. Knock-down of Epha2 led to the spontaneous differentiation of mouse ESCs, underscoring a pivotal role of EPHA2 in maintaining an undifferentiated cell state. Further investigations revealed a strong correlation between EPHA2 and OCT4 expression during the differentiation of both mouse and human PSCs. Notably, removing EPHA2+ cells from mouse ESC-derived hepatic lineage reduced tumor formation after transplanting them into immune-deficient mice. Similarly, in human iPSCs, a larger proportion of EPHA2+ cells correlated with higher OCT4 expression, reflecting the pattern observed in mouse ESCs. Conclusively, EPHA2 emerges as a potential marker for selecting undifferentiated stem cells, providing a valuable method to decrease tumorigenesis risks after stem-cell transplantation in regenerative treatments.