This review article examines how stem cell therapies can cure various diseases and injuries while also discussing the difficulties and moral conundrums that come with their application. The article focuses on the revolutionary developments in stem cell research, especially the introduction of gene editing tools like CRISPR-Cas9, which can potentially improve the safety and effectiveness of stem cell-based treatments. To guarantee the responsible use of stem cells in clinical applications, it is also argued that standardizing clinical procedures and fortifying ethical and regulatory frameworks are essential first steps. The assessment also highlights the substantial obstacles that still need to be addressed, such as the moral dilemmas raised by the use of embryonic stem cells, the dangers of unlicensed stem cell clinics, and the difficulties in obtaining and paying for care for patients. The study emphasizes how critical it is to address these problems to stop exploitation, guarantee patient safety, and increase the accessibility of stem cell therapy. The review also addresses the significance of thorough clinical trials, public education, and policy development to guarantee that stem cell research may fulfill its full potential. The review concludes by describing stem cell research as a promising but complicated topic that necessitates a thorough evaluation of both the hazards and the benefits. To overcome the ethical, legal, and accessibility obstacles and eventually guarantee that stem cell treatments may be safely and fairly included in conventional healthcare, it urges cooperation between the scientific community, legislators, and the general public.

Spinal cord injury (SCI) results in chronic motor deficits and intractable neuropathic pain, driven by neuroinflammation and impaired tissue repair. Current therapies inadequately address these multifaceted challenges. This study investigated the therapeutic effects of human adipose-derived mesenchymal stem cells (hADSCs) transplantation combined with green light (GL) therapy to modulate inflammation, enhance autophagy, and facilitate functional restoration post-SCI.

Neurological disorders, ranging from common conditions like Alzheimer's disease that is a progressive neurodegenerative disorder and remains the most common cause of dementia worldwide to rare disorders such as Angelman syndrome, impose a significant global health burden. Altered facial expressions are a common symptom across these disorders, potentially serving as a diagnostic indicator. Deep learning algorithms, especially convolutional neural networks (CNNs), have shown promise in detecting these facial expression changes, aiding in diagnosing and monitoring neurological conditions.

The tumor microenvironment (TME) plays a pivotal role in cancer progression, with cancer-associated fibroblasts (CAFs) significantly influencing tumor behavior. Especially, elevated COX2 expressing fibroblasts within the TME, notably in collagen-dense tumors like breast cancer, has been recently emphasized in the literature. However, the specific effect of COX2-expressing CAFs (COX2+ CAFs) on neighboring cells and their consequent role in cancer progression is not fully elucidated.

The results of this research contribute to the LifeSaver project, which focuses on reducing neonatal and infant mortality resulting from preterm births. The project aims to create an in vitro system simulating prenatal conditions to screen and analyze chemicals and pharmaceuticals, establishing scientifically justified regulations for their use during pregnancy. Because several papers have recently identified data inconsistencies in pre-clinical studies, a key part of the project involves optimizing cellular cytotoxicity assays to enhance the reliability of pharmacological and toxicity screening for drugs and environmental contaminants.

Chronic back pain and disability are primarily caused by intervertebral disc degeneration (IDD) that requires novel therapies to regenerate the nucleus pulposus (NP) and restore disc function. In this study, a bioengineered thermo-sensitive injectable hydrogel composed of co-polymeric poly-N-isopropyl acrylamide-grafted-chondroitin sulfate cross-linked with sodium alginate microspheres (PNIA-g-CS-NaA Ms: denote HMs) loaded with growth differentiation factor 5 (GDF-5), to stimulate Nucleus Pulposus cells (NPCs) activity and promote intervertebral disc (IVD) regeneration. The Low critical solution temperature (LCST) of PNIA-g-CS was 31.8 and 32.3 °C at 5% (w/v) and 15% (w/v), respectively. In the in vitro study, GDF-5-loaded hydrogel (1 mg/mL) marginally enhanced NPC proliferation and reduced inflammatory cytokines (TNF-α, IL-6, IL-1β) after 24 h. HMs-GDF-5 combined with Adipose-Derived Mesenchymal Stem Cells (ADMSCs) was delivered to NP tissue using a minimally invasive technique, promoting NP regeneration in rats. At 8 weeks, significant upregulation of COL-II and ACAN proteins and mRNA expressions was observed. X-ray imaging showed disc height recovery and increased water content, while histology revealed partial restoration of NPCs and matrix. The outcomes show that the biodegradable hydrogel could be used as a potential therapeutic agent for IVD repair.

Glioblastoma (GBM) is a highly resistant tumor, and targeting its bioenergetics could be a potential treatment strategy. GBM cells depend on cytosolic nicotinamide adenine dinucleotide (NADH), which is transported into the mitochondria via the malate-aspartate shuttle (MAS) for ATP production. N-phenylmaleimide (KN612) is a MAS inhibitor that targets SLC25A11, an antiporter protein of the MAS. Therefore, this study investigated the effects of KN612 in GBM treatment using in vitro and in vivo models.

Bone defects are common orthopedic conditions, and due to the limited regenerative capacity of bone tissue, their repair remains a challenge in orthopedic surgery. Mesenchymal stem cells (MSCs) have demonstrated strong potential for osteogenic differentiation; however, their efficiency in vivo remains restricted, particularly in terms of differentiation and migration. Photobiomodulation (PBM), a non-invasive therapeutic technique, has shown great promise in promoting stem cell differentiation. In this study, we cultured human umbilical cord mesenchymal stem cells (hUCMSCs) in vitro and treated them with 635/808 nm laser light. We measured alkaline phosphatase (ALP) activity, mineralized nodule formation, and the expression of osteogenesis-related genes and factors after 7, 14, and 21 days. The results showed that PBM treatment significantly enhanced hUCMSC proliferation and osteogenic differentiation. The mechanism behind this effect involves PBM activating the upstream Akt signaling pathway, increasing P-Akt expression, and elevating reactive oxygen species (ROS) levels to induce mild oxidative stress. This process enhances ALP activity, mineralized nodule formation, and the expression of osteogenesis-related genes and factors, thus promoting the osteogenic differentiation of hUCMSCs.

DNA polymerase γ (POLγ), responsible for mitochondrial DNA replication, consists of a catalytic POLγA subunit and two accessory POLγB subunits. Mutations in POLG, which encodes POLγA, lead to various mitochondrial diseases. We investigated the most common POLG mutations (A467T, W748S, G848S, Y955C) by characterizing human and mouse POLγ variants. Our data reveal that these mutations significantly impair POLγ activities, with mouse variants exhibiting milder defects. Cryogenic electron microscopy highlighted structural differences between human and mouse POLγ, particularly in the POLγB subunit, which may explain the higher activity of mouse POLγ and the reduced severity of mutations in mice. We further generated a panel of mouse models mirroring common human POLG mutations, providing crucial insights into the pathogenesis of POLG-related disorders and establishing robust models for therapeutic development. Our findings emphasize the importance of POLγB in modulating the severity of POLG mutations.

Stem cell-derived islet cell therapy can effectively treat type 1 diabetes, but its efficacy is hindered by low oxygen supply post-transplantation, particularly in subcutaneous spaces and encapsulation devices, leading to cell dysfunction. The response to hypoxia and effective strategies to alleviate its detrimental effects remain poorly understood. Here, we show that β cells within stem cell-derived islets gradually undergo a decline in cell identity and metabolic function in hypoxia. This is linked to reduced expression of immediate early genes (EGR1, FOS, and JUN), which downregulates key β cell transcription factors. We further identified genes important for maintaining β cell fitness in hypoxia, with EDN3 as a potent player. Elevated EDN3 expression preserves β cell identity and function in hypoxia by modulating genes involved in β cell maturation, glucose sensing and regulation. These insights improve the understanding of hypoxia's impact on stem cell-derived islets, offering a potential intervention for clinical applications.

The persistently low success rate of human in vitro fertilization (IVF) remains a major clinical challenge, despite significant technological advancements. While culture media composition is known to influence outcomes, the specific components affecting embryonic development are poorly understood. In this study, we identify N-glycolylneuraminic acid (Neu5Gc), a foreign sialic acid contaminant prevalent in animal-derived IVF media components, as a micro-environmental factor triggering developmental arrest. We demonstrate that Neu5Gc accumulates in arrested human embryos via endocytosis and upregulates p53, leading to caspase-3/PARP -dependent apoptotic pathways. This mechanism was validated in human embryonic stem cells (hESCs) and zebrafish embryos, with antibody-mediated Neu5Gc neutralization rescuing developmental defects. Our findings not only elucidate a novel pathway contributing to IVF inefficiency but also provide actionable insights for optimizing culture media formulations.

Nonsense-mediated mRNA decay (NMD) eliminates transcripts containing premature termination codons (PTCs), thereby preventing errors in protein synthesis. Serine/Threonine-protein kinase SMG1 is a crucial kinase for NMD response, interacting with other regulatory proteins such as SMG8 and SMG9. We identified a de novo heterozygous variant in SMG1 p.Gln2398Glu (c.7192C>G) in a patient with global developmental delay, facial dysmorphism, and oculomotor apraxia. Thus, stem cell models with SMG1 mutations using gene editing technology were established to address the functional consequences of this mutation. While mutations causing the reduction in SMG1 gene dosage by alterations in splicing (c.7192_7194delinsGAA; GAA/+) or frameshift (c.4331_4337del; KO/+) led to a mild but significant reduction of NMD activity, NMD activity was not altered in cells with the SMG1 GAG/+ mutation. Furthermore, cortical organoids from hPSCGAA/+ exhibited size reduction compared to the control (CTL) or GAG/+, suggesting that reduced NMD activity can affect nervous system development. These findings suggest that hypomorphic SMG1 mutations can cause reduced NMD activity and subsequent biological responses, while the mutation found in the patient alone may not be sufficient to induce pathological symptoms.

Skeletal stem cells (SSCs) have been isolated from various tissues, including periosteum and bone marrow, where they exhibit key functions in bone biology and hematopoiesis, respectively. The role of periosteal SSCs (P-SSCs) in bone regeneration and healing has been extensively studied, but their ability to contribute to the bone marrow stroma is still under debate. In the present study, we characterized a mouse whole bone transplantation model that mimics the initial bone marrow necrosis and fatty infiltration seen after injury. Using this model and a lineage tracing approach, we observed the migration of P-SSCs into the bone marrow after transplantation. Once in the bone marrow, P-SSCs are phenotypically and functionally reprogrammed into bone marrow mesenchymal stem cells (BM-MSCs) that express high levels of hematopoietic stem cell niche factors such as Cxcl12 and Kitl. In addition, using ex vivo and in vivo approaches, we found that P-SSCs are more resistant to acute stress than BM-MSCs. These results highlight the plasticity of P-SSCs and their potential role in bone marrow regeneration after bone marrow injury.

While sexual reproduction is a general feature of animals, fissiparity and budding are relatively uncommon modes of asexual reproduction by which a fragment from a parent becomes an independent organism. Unlike unitary development, tumor cells can be included in the detached fragment destined to become offspring. Although fragmentation facilitates the vertical transmission of parental tumor cells to nascent progeny, this process requires significantly fewer cell replications than development from a zygote. The former is a risk factor for cancer, while the latter reduces oncogenic mutations during replication, indicating that two opposite effects of carcinogenesis are involved in fragmentation. If fragmentation can significantly reduce the number of cell replications for the development and a small portion of parental cancer is transmitted to the offspring during fragmentation, consecutive fragmentation across generations can gradually diminish the cancer risk of offspring, which I term fragmentational purging. On the other hand, consecutive fragmentation may aggravate the cancer risk of the progeny, a process of fragmentational accumulation. The model results imply that fragmentational purging does not necessarily guarantee the evolution of fragmentation, nor does fragmentational accumulation ensure its exclusion. Other relevant factors including juvenile susceptibility of sexual reproduction and loss of genetic diversity stemming from asexual reproduction can influence the selective advantage of fragmentation. Furthermore, owing to the common features of stemness and self-renewal, the existence of pluripotent adult stem cells required for fragmentation could be coupled with elevated cancer risk. The model results across diverse parameters and the associated mathematical analyses highlight multifaceted evolutionary trajectories toward fragmentation. Further investigation of cancer-suppression strategies that fragmentational animals employ could provide insights into regenerative medicine and cancer therapy.

Osteogenic differentiation of mesenchymal stem cells (MSCs) was strongly correlated with the progression of congenital tibial pseudoarthrosis (CPT). Activation of ferroptosis inhibited osteogenic differentiation of MSCs. ELAV-like RNA binding protein 1 (ELAVL1) is a key factor in promoting ferroptosis. This study aimed to elucidate the mechanism of ELAVL1 in the osteogenic differentiation of CPT periosteum-derived MSCs. Osteogenic differentiation of CPT periosteum-derived MSCs was detected by ARS and ALP staining. Fe2+ content and lipid reactive oxygen species content were measured using commercial kits. Molecular interactions were verified using RIP, RNA pulldown, and Co-IP. The ubiquitination level of homeobox gene D8 (HOXD8) was detected using Co-IP. Expression of ELAVL1 and tripartite motif containing 21 (TRIM21) was upregulated in CPT periosteum-derived MSCs, whereas HOXD8 expression was downregulated. Moreover, knockdown of ELAVL1 or TRIM21 inhibited ferroptosis and promoted osteogenic differentiation of CPT MSCs. TRIM21 overexpression reversed the effect caused by knockdown of ELAVL1. Mechanistically, ELAVL1 upregulated TRIM21 by increasing the stability of TRIM21, which ubiquitinated and degraded HOXD8. ELAVL1 bound to TRIM21, which promoted ubiquitination and degradation of HOXD8, thereby promoting ferroptosis to inhibit osteogenic differentiation of CPT MSCs.

Acute kidney injury (AKI) has a high morbidity and mortality rate but can only be treated with supportive therapy in most cases. The diagnosis of AKI is mainly based on serum creatinine level and urine volume, which cannot detect kidney injury sensitive and timely. Therefore, new diagnostic and therapeutic molecules of AKI are being actively explored. Extracellular vesicles (EVs), secreted by almost all cells, can originate from different parts of the kidney and mediate intercellular communication between various cell types of nephrons. At present, numerous successful EV-based biomarker discoveries and treatments for AKI have been made, such as the confirmed diagnostic role of urine-derived EVs in AKI and the established therapeutic role of mesenchymal stem cell-derived EVs in AKI have been confirmed; however, these related studies lack a full discussion. In this review, we summarize the latest progression in the profound understanding of the functional role of EVs in AKI caused by various etiologies in recent years and provide new insights into EVs as viable biomarkers and therapeutic molecules for AKI patients. Furthermore, the current challenges and prospects of this research area are briefly discussed, presenting a comprehensive overview of the growing foregrounds of EVs in AKI.

Dominant defects in CHCHD10, a mitochondrial intermembrane space protein, lead to a range of neurological and muscle disease phenotypes including amyotrophic lateral sclerosis. Many patients present with spinal muscular atrophy Jokela type (SMAJ), which is caused by heterozygous p.G66V variant. While most disease variants lead to aggregation of CHCHD10 and activation of proteotoxic stress responses, the pathogenic mechanisms of the p.G66V variant are less clear. Here we report the first homozygous CHCHD10 patient, and show that the variant dosage dictates the severity of the motor neuron disease in SMAJ. We demonstrate that the amount of the mutant CHCHD10 is reduced, but the disease mechanism of p.G66V is not full haploinsufficiency as residual mutant CHCHD10 protein is present even in a homozygous state. Novel knock-in mouse model recapitulates the dose-dependent reduction of mutant CHCHD10 protein and the slow disease progression of SMAJ. With metabolome analysis of patients' primary fibroblasts and patient-specific motor neurons, we show that CHCHD10 p.G66V dysregulates energy metabolism, leading to altered redox balance and energy buffering by creatine metabolism.

ATP-dependent nucleosome remodeling complexes of the imitation switch (ISWI) family slide and space nucleosomes. The ISWI ATPase subunit forms obligate complexes with accessory subunits whose mechanistic roles remain poorly understood. In baker's yeast, the Isw2 ATPase subunit associates with Itc1, the orthologue of human ACF1/BAZ1A. Prior data suggested that the genomic deletion of the 374 N-terminal amino acids from Itc1 (hereafter called itc1ΔN) leads to a gain-of-toxic-function phenotype with severe growth defects in the BY4741 genetic background, possibly due to defective nucleosome spacing activity of the mutant complex.

With the discovery of intercellular mitochondrial transfer, the intricate mitochondrial regulatory networks on stem cell fate have aroused intense academic interest. Apart from capturing freely released mitochondria from donor cells, stem cells are able to receive mitochondria through tunneling nanotubes (TNTs), gap junctional channels (GJCs) and extracellular vesicles (EVs), especially when undergoing stressful conditions such as inflammation, hypoxia, chemotherapy drug exposure, and irradiation. Stem cells that are potentiated by exogenous mitochondria show enhanced potential for proliferation, differentiation, and immunomodulation. The well-tolerated nature of either autogenous or allogenous mitochondria when locally injected in the human ischemic heart has validated the safety and therapeutic potential of mitochondrial transplantation. In children diagnosed with mitochondrial DNA deletion syndrome, functional improvements have been observed when empowering their hematopoietic stem cells with maternally derived mitochondria. Apart from the widely investigated applications of mitochondrial transfer in ischemia-reperfusion injury, neurodegenerative diseases and mitochondrial diseases etc., therapeutic potentials of mitochondrial transfer in tissue repair and regeneration are equally noteworthy, though there has been no systematic summary in this regard.This review analyzed the research and development trends of mitochondrial transfer in stem cells and regenerative medicine over the past decade from a bibliometric perspective, introduced the concept and associated mechanisms of mitochondrial transfer, summarized the regulations of intercellular mitochondrial transfer on stem cell fate. Finally, the therapeutic application of mitochondrial transplantation in diseases and tissue regeneration has been reviewed, including recent clinical studies related to mitochondrial transplantation.Mitochondrial transfer shows promise in modifying and reshaping the cellular properties of stem cells, making them more conducive to regeneration. Mesenchymal stem cells (MSCs)-derived mitochondria have shown multifaceted potential in promoting the revitalization and regeneration of cardiac, cutaneous, muscular, neuronal tissue. This review integrates novel research findings on mitochondrial transfer in stem cell biology and regenerative medicine, emphasizing the crucial translational value of mitochondrial transfer in regeneration. It serves to underscore the significant impact of mitochondrial transfer and provides a valuable reference for further exploration in this field.