Stem Cells International最新文献

Background: Severe osteonecrosis of the femoral head (ONFH) secondary to corticosteroid therapy in symptomatic, hematological young patients currently has no therapeutic alternative, and early total hip replacement (THR) is a high-risk intervention in those patients.

Objectives: To evaluate feasibility, safety, and early efficacy of allogeneic expanded mesenchymal stromal cells (MSCs) in a pilot clinical trial.

Methods: Pilot phase 1 open, noncontrolled, nonrandomized clinical trial evaluating the bone regeneration capacity in seven hips from four patients (young females 11-19 year old) with symptomatic, severe bilateral femoral head osteonecrosis (secondary to corticosteroid therapy), 1 year after being surgically treated with 140 × 10⁶ allogenic MSC plus forage.

Results: The proposed therapy proved feasibility, safety at 1 and 4 years (no related serious adverse events [SAEs]), and early efficacy (nonsignificant) in the case analysis (5/7 hips avoiding THR at 4 years).

Conclusions: The implantation of expanded allogeneic MSC in young patients to prevent conversion to a THR or collapse of the femoral head due to severe osteonecrosis is feasible without safety concerns in the longer-term follow-up (FU) upto 4 years. Trial Registration: EudraCT number: 2018-000886-35.

Background: Mesenchymal stromal cells (MSCs) support tissue repair in osteoarthritis (OA), with migration to damaged tissue being a key strategy in in situ tissue engineering. Their regenerative potential depends on factors such as differentiation, level of senescence, and responsiveness to signaling molecules. However, previous findings on these properties of OA MSCs remain inconclusive. This study integrates multiple aspects and tests feasibility using a well-characterized chemoattractant.

Methods and results: MSCs from non-OA donor (ND) and OA donor were characterized for their trilineage differentiation potential as well as for their senescence level by (immune-) histochemistry, RT-qPCR, microarray analysis, and a bead-based immunoassay for cell culture supernatants. No difference in differentiation and senescence level was observed, the latter being indicated by a similar activity of β-Galactosidase (β-gal), gene expression profiles of cyclin-dependent kinase (CDKN) inhibitor 2A (CDKN2A), CDKN inhibitor 1A (CDKN1A), sirtuin 1 (SIRT1), and matrix metallopeptidase 1 (MMP1), as well as secreted cytokines. Chemokine receptors in OA MSCs were detected using immunohistochemistry and RT-qPCR. Expression of CCR1-CCR7, CCR9, and CXCR1-CXCR6 in OA MSCs was confirmed on gene and protein levels. Both OA and ND MSCs migrated toward 1000 nM CCL25, as evaluated via a Boyden chamber assay. Subsequent genome-wide microarray analysis of OA MSCs after treatment with 1000 nM CCL25 corroborated its influence on migration, proliferation, apoptosis, and differentiation as defined by Gene Ontology terms (GO terms). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis confirmed this broad impact and emphasized the role of cytokine-cytokine-receptor interaction and metabolic pathways.

Conclusion: Our data indicate that OA MSCs retain their differentiation potential and do not exhibit an increased senescent phenotype. Their chemokine receptor profile is conducive of migration, and both OA and ND MSCs respond to CCL25, highlighting the potential of OA MSCs for directed in situ repair.

Human dental pulp stem cells (hDPSCs) hold significant promise for bone regeneration, yet efficient osteogenic induction remains challenging. Phosphorylated oligosaccharides of calcium (POs-Ca), a novel calcium salt derived from potato starch, has recently attracted attention for its remineralization capabilities and potential to promote stem cell differentiation. Here, we investigated the impact of POs-Ca on the osteogenic differentiation of hDPSCs and its underlying mechanism. Isolated hDPSCs were characterized via flow cytometry based on mesenchymal surface markers. Biocompatibility and osteogenic differentiation were assessed via Cell Counting Kit-8 (CCK-8) assay, alkaline phosphatase (ALP) activity, Alizarin Red S staining, and protein levels of osteogenic (Collagen I, DSPP, DMP1, and RUNX2). Intracellular Ca²⁺ flux was monitored using Fluo-4 AM, while AMP-activated protein kinase (AMPK) signaling and autophagic flux were analyzed by western blot (p-AMPK, p-ULK1, and light chain 3 (LC3)-II), TEM, and LC3-GFP imaging. Mechanistic studies employed verapamil (Ca²⁺ channel blocker), Compound C (CC;AMPK inhibitor), and chloroquine (CQ;autophagy inhibitor). POs-Ca (5 mg/mL) exhibited excellent biocompatibility and significantly promoted osteogenic differentiation, as evidenced by a 3.22-fold increase in ALP activity and markedly enhanced mineralized nodule formation as shown by Alizarin Red S staining. Mechanistic studies revealed that POs-Ca triggers rapid intracellular Ca²⁺ influx, activating the AMPK pathway and inducing autophagic flux. Pharmacological inhibition established the essential causality of this cascade: verapamil abolished osteogenic enhancement, while CC and CQ suppressed ALP activity, mineralization, and osteogenic marker expression. Notably, CQ reciprocally attenuated POs-Ca-induced Ca²⁺ influx, revealing novel bidirectional Ca²⁺-autophagy crosstalk. In conclusion, POs-Ca might promote hDPSCs osteogenesis via a calcium influx-driven AMPK-autophagy axis, providing a foundation for novel biomaterials that exploit physiological calcium signaling. These findings offer immediate translational potential for developing minimally invasive, cost-effective strategies in dental pulp regeneration and bone defect repair.

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) ameliorate motor deficits in cerebral palsy (CP), but the effect of injection frequency remains unclear. Moreover, most studies have focused on mild CP models (unilateral carotid artery occlusion [UCAO] model). This study explored the effect and mechanism of hUC-MSCs in a rat model of moderate-to-severe CP (bilateral carotid artery occlusion [BCAO] model). On postnatal Day 4 (P4), Wistar rat pups underwent BCAO induction. Subsequently, they received either a single intrathecal injection of hUC-MSCs on P21 or repeated injections on P21, P28, P35, and P42. Motor performance was assessed using the rotarod and front-limb suspension tests, while neuronal regeneration and inflammation were evaluated via biomarkers including neuronal nuclear antigen (NeuN), ionized calcium-binding adapter molecule-1 (Iba-1), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and brain-derived neurotrophic factor (BDNF). P18 model screening confirmed that the BCAO model resulted in more severe brain damage and motor impairment than the UCAO model. After injection of lentivirally transfected hUC-MSCs, it was found that hUC-MSCs could nest in the damaged area and survive for at least 3 days. Administration of hUC-MSCs following BCAO modeling led to notable improvements in both behavioral performance and histological outcomes. Furthermore, repeated injections offered greater therapeutic benefits compared to single injection. It indicated that the efficacy of repeated injections of hUC-MSCs in the treatment of moderate-to-severe CP was superior to that of single injection. Its mechanism was related to the improvement of damaged myelin structure, reduced immunoinflammatory responses, and increased neurotrophic support.

Globally, stroke stands as a principal cause of death and disability, presenting formidable challenges in rehabilitation. Conventional therapeutic modalities often fail to restore functional capabilities fully, underscoring the need for innovative treatment strategies. Stem cell therapy emerges as a revolutionary approach, capitalizing on the regenerative capabilities of stem cells to improve neurological function poststroke. This review evaluates the roles of various stem cell types-mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs)-in the realm of stroke recovery. It elucidates their distinct biological mechanisms, evaluates their therapeutic impact based on clinical trial data, and discusses their efficacy in fostering neural repair and recovery. MSCs are particularly noted for their role in immunomodulation and promotion of angiogenesis and neurogenesis, with clinical evidence supporting their safety and effectiveness in stroke recovery. NSCs are lauded for their ability to differentiate into diverse neural lineages. They integrate into neural circuits to enhance synaptic connectivity and neuroplasticity. iPSCs, known for their versatility, can be tailored to patient-specific needs and are shown in preclinical settings to reduce infarct size and promote the survival of neuronal cells. However, the field grapples with challenges, including optimizing stem cell transplantation timing, precision in cell delivery, integration efficiency, and immune system compatibility. These issues call for harmonization of methodologies across ongoing studies to ensure the reliability and consistency of therapeutic outcomes. This review highlights the promising future and challenges of stem cell therapy for treatment of stroke.

Repair of large soft tissue defects by tissue expansion often faces difficulties in skin expansion. Particularly in those who have lost a significant amount of skin and subcutaneous tissue due to total mastectomy, tissue expansion may result in skin breakdown and exposure of the expander. Subcutaneous fat construction by autologous fat grafting before expansion seems to assist skin expansion. We hypothesize that it may be related to the adipose-derived stem cells (ADSCs) in subcutaneous fat. In this study, we confirmed this phenomenon through animal experiments and provided a preliminary investigation of the possible mechanisms involved. Four groups were designed for the experiment, experimental group (EG) for autologous fat flap transfer and tissue expansion. Fat grafting control group (FGCG), where only autologous fat flap transfer was performed without tissue expansion. Tissue expansion control group (TECG) did not perform autologous fat flap transfer but only skin tissue expansion on the back. Blank control group (BCG) has not received any surgery. In each group of 20 rats, skin, and fat flaps of the dilated area were sampled at four time points (7, 14, 21, and 28 days, n = 5), and the immediate skin retraction rate of the expanded area in the EG and TECG groups was measured to evaluate the expansion effect. GFP⁺ADSCs were observed to demonstrate whether they were facilitated by tissue expansion and migrated from autologous fat flaps to skin. Our study supported that fat layer construction prior to skin expansion helps to promote skin growth. The promotion may be related to the migration of ADSCs from adipose to dermis by compression, and ADSCs migrating to dermis further promote skin stretching through direct differentiation or paracrine cytokines to promote cell proliferation and collagen synthesis.

Thoracic aortic dissection (TAD) is a life-threatening condition characterized by medial degeneration and vascular smooth muscle cell (VSMC) dysfunction, with no effective medical therapy currently available. The underlying pathological mechanisms of TAD remain incompletely understood. In this study, we used a nonintegrated episomal vector-based reprograming system to generate induced pluripotent stem cells (iPSCs) from TAD patients and healthy controls. Both TAD and normal iPSCs expressed key pluripotency markers and were capable of differentiating into the three germ layers in vitro. These iPSCs were differentiated into vascular smooth muscle cells (VSMCs) through a mesodermal intermediate for disease modeling. VSMCs derived from both TAD and normal iPSCs expressed smooth muscle α-actin (α-SMA), calponin (CNN), and SM22α. However, TAD-iPSC-derived VSMCs exhibited significantly reduced contraction in response to carbachol stimulation compared to their normal counterparts. Whole-exome sequencing identified a mutation in the COL4A2 gene (c.392G > T, p. R131M) in TAD-iPSCs. This mutation was associated with reduced collagen IV expression and increased expression of collagen I and III in TAD-VSMCs, both with and without TGF-β stimulation. Furthermore, noncanonical TGF-β signaling was hyperactivated in TAD-VSMCs, accompanied by elevated MMP9 expression. This patient-specific iPSC model reveals key dysfunctions in VSMC contractility, extracellular matrix (ECM) protein expression, and dysregulated TGF-β signaling, which may contribute to TAD pathogenesis. Our findings provide new insights into the molecular mechanisms driving TAD and offer a platform for future therapeutic development.

[This corrects the article DOI: 10.1155/sci/8681205.].

Skin aging is a multifaceted biological process driven by genetic and environmental factors, in which epidermal stem cells (EpSCs) decrease in number and decline in function. Emerging evidence indicates that epigenetic modifications play a crucial regulatory role in the aging process. Therefore, elucidating the epigenetic mechanisms in aging will provide novel avenues for developing strategies to delay aging. In this review, we explore the epigenetic mechanisms regulating EpSCs function, namely DNA methylation (DNAm), histone modifications, noncoding RNA, and their dysregulation and the resulting series of manifestations during aging. Furthermore, we introduce epigenetic clocks such as Horvath's and the skin-specific VisAgeX to quantify these age-related changes, which provide precise biomarkers of biological age, enabling the assessment of both aging progression and therapeutic outcomes. Finally, we summarize emerging interventions targeting these epigenetic disruptions. Advancing these epigenetic modulations holds significant potential for cutaneous antiaging and fostering innovative dermatological treatments.

Apoptotic vesicles (ApoVs) have garnered considerable attention within the realm of tissue regeneration research, necessitating a comprehensive bibliometric analysis to delineate current international trends and to map out historical and contemporary developments in this domain.

Methods: This study conducted a bibliometric analysis leveraging data sourced from the SCI-Expanded Web of Science (WOS) database. The analysis encompassed publications from October 1, 1991, to December 31, 2023. A total of 1209 articles focusing on ApoVs for tissue regeneration were scrutinized, considering attributes such as publication year, journal, author, institution, country/region, references, and keywords. Coauthorship, cocitation, co-occurrence analyses, network visualizations were generated using VOSviewer and CiteSpace.

Results: The analysis indicated a steady annual rise in global publications pertaining to ApoVs for tissue regeneration. The United States emerged as the foremost contributor, with the highest citation count and H-index. Furthermore, University of Tehran Medical Sciences was pinpointed as the most prolific institution. The journal International Journal of Molecular Sciences issued the largest account of articles on this topic. Notable subtopics such as "regenerative medicine," "delivery," and "mesenchymal stem cells" are poised to become significant research focal points in the near future.

Conclusions: Over the past 30 years, research on ApoVs for tissue regeneration has witnessed substantial growth, mirroring increasing collaboration across various countries and institutions. This study illuminates trends, collaboration patterns, research hotspots, and future trajectories in the field, providing valuable insights for researchers and practitioners.