STEM CELLS最新文献

Hematopoietic stem cell (HSC) transplantation is a potentially curative option for patients with hematologic malignancies, but donor shortages impact graft availability. Umbilical cord blood (UCB) is a viable alternative source of HSC, however the limited numbers present in a single unit have spurred efforts to expand HSC ex vivo. We previously demonstrated that the addition of valproic acid (VPA), an anti-convulsive drug, to CB cell cultures promotes maintenance of functional HSC, but not expansion. However, it has been proposed that VPA primarily induces mitochondrial reprogramming of mature CD34+CD90- cells to more primitive CD34+CD90+ cells, rather than the replication of CD34+CD90+ cells in culture. To determine which fraction of the CD34+CD90+ cells present after culture in VPA were derived from CD34+CD90- vs. CD34+CD90+ cells, we examined the functionality of CD34+CD90+ cells derived from each flow cytometry-sorted population. During culture in VPA there was a significant increase in CD34+CD90+ cell number; the majority arising from pre-existing CD34+CD90+ cells, with minimal contribution from CD34+CD90- cells. Colony-forming unit (CFU) assays revealed reduced plating efficiency and xeno-transplantation studies demonstrated diminished in vivo hematopoietic reconstitution potential of CD34+CD90+ cells derived from relatively committed CD34+CD90- cells. Our findings indicate that while VPA supports CD34+CD90+ cell expansion, the CD34+CD90+ cells derived from CD34+CD90- cells are functionally more differentiated than those derived directly from CD34+CD90+ cells, with increased mitochondrial mass and membrane potential, but reduced regenerative potential. These results emphasize the need for functional assessments of culture-expanded HSCs to accurately determine their therapeutic potential.

Osteoradionecrosis of the jaws (ORNJ) is a severe aseptic complication of high-dose radiotherapy for head-and-neck cancers, characterized by chronic jawbone necrosis, functional impairment, and poor responses to traditional treatments (e.g., hyperbaric oxygen, surgical resection) that fail to address its root pathophysiology (microcirculatory impairment, bone metabolism dysfunction). Its incidence is 1.2%-40% in patients receiving >60 Gy radiotherapy, especially with concurrent trauma. In recent years, stem cell therapy has garnered attention as a potential treatment for a variety of bone-related disorders, including the repair of bone defects, treatment of osteoarthritis, and mitigation of osteoporosis. Evidence from preclinical studies indicates that local transplantation of mesenchymal stem cells in rodent models of ORNJ significantly increases bone volume and bone mineral density. The therapeutic efficacy is primarily attributed to the cells' capacity for multidirectional differentiation, paracrine signaling, and immunomodulatory functions, highlighting their substantial potential for clinical translation. This narrative review synthesizes studies on stem cell therapy for ORNJ published from 2004 to 2024 (PubMed, Medline, Cochrane), with a focus on original research published in the most recent decade (2014-2024) to reflect the latest advances. This review consolidates ORNJ pathogenesis and stem cell mechanisms, identifies research gaps, and guides future efforts to standardize protocols and advance clinical translation.

Background: Umbilical cord blood (UCB) and umbilical cord tissue (UCT) are non-invasive, readily available sources of stem cells with significant potential for regenerative medicine and hematopoietic transplantation. While hematopoietic stem cells from UCB and mesenchymal stem cells from both UCB and UCT are clinically applied, other cord-derived populations remain under investigation, offering novel therapeutic opportunities alongside translational challenges.

Main body: This review synthesizes current knowledge on stem cell populations derived from UCB and UCT. Hematopoietic and mesenchymal stem cells have established clinical roles, whereas unrestricted somatic stem cells, embryonic-like stem cells, MUSE cells, and multipotent progenitor cells show preclinical promise. These populations differ in differentiation potential, therapeutic application, and biological characteristics. Translational barriers include limited cell numbers, variable engraftment, immune compatibility, and challenges in long-term preservation. Emerging strategies, such as ex vivo expansion, co-transplantation, and nanoparticle-assisted delivery, aim to enhance efficacy, precision, and safety.

Conclusion: This Narrative review highlights both opportunities and challenges of umbilical cord stem cell therapies. Standardized protocols, interdisciplinary collaboration, and continued innovation are essential to optimize clinical outcomes and fully realize the translational potential of these diverse populations.

The precise timing of stem cell specification and niche formation during murine incisor development is poorly understood, and it is unclear whether these processes occur simultaneously or in a sequential manner. Functional dental epithelial stem cells are marked by the expression of Sox2, a transcription factor that is broadly expressed in the dental epithelium at the dentition onset and restricted to stem cells in fully developed incisor. Using genetic lineage tracing in Sox2CreERT2/+; R26RmT/mGand Sox2CreERT2/+; R26RtdT/+embryos along with a single-cell RNA sequencing at different stages of incisor development, we investigated the timing of the stem cell specification and its temporal relationship with niche formation. Our results reveal the presence of a Sox2-expressing stem cell-like population prior to formation of the functional niche. These cells localize to the leading edge of the advancing incisor epithelium where they are maintained in an undifferentiated state. Our data demonstrate presence of actomyosin network and a generation of a contractile tension which helps confine Sox2+ stem cells to the leading edge. This mechanical confinement likely plays an important role in maintaining their stemness until the niche is functionally and structurally established. Partial or complete disruption of the actomyosin network disables the clustering of Sox2-expressing cells, potentially triggering their premature differentiation, and ultimately leads to impaired formation of the functional stem cell niche and abnormal growth of the incisor.

Background: Mesenchymal stromal/stem cell (MSC) transplantation has emerged as a promising therapeutic strategy for managing cutaneous scarring, an issue associated with significant aesthetic and functional morbidity. This systematic review evaluates the potential of MSCs to modulate scarring, highlighting their efficacy and distinct mechanisms from traditional scar treatments.

Materials and methods: The review adheres to the PRISMA guidelines. We followed a prospectively registered protocol and conducted comprehensive searches in the PubMed and EMBASE databases. Eleven studies, including preclinical and clinical trials, met the inclusion criteria. Study quality was assessed using the ROBINS-I and Cochrane Risk of Bias 2 tools.

Discussion: MSC and MSC-conditioned medium therapies derived from adipose tissue, bone marrow, or the umbilical cord demonstrated significant improvements in scar appearance, reductions in thickness and volume, and beneficial remodeling of collagen structures. MSC treatment positively influenced inflammatory and immunomodulatory responses, as reflected by the regulation of cytokines and fibrotic biomarkers. However, the heterogeneity in methodologies, MSC sources, and administration routes limits the ability to make conclusive statements. Furthermore, insufficient transparency in MSC preparation challenges clinical reproducibility and application.

Conclusion: MSC therapy is becoming increasingly important in regenerative medicine. Based on our findings, MSC therapy demonstrates potential in scar remodeling through antifibrotic and immunomodulatory effects. However, robust randomized controlled trials and standardized product reporting are essential to confirm long-term efficacy and safety, improve reproducibility, and facilitate clinical translation. Advancements in these areas will define the future role of MSC therapies in managing scarring.

Introduction: The sustained production of blood and immune cells is driven by a pool of hematopoietic stem cells (HSCs) and their offspring. Due to the intrinsic heterogeneity of HSCs, the composition of emergent clones changes over time, leading to a reduced clonality in aging mice and humans. Theoretical analyses suggest that clonal conversion rates and clonal complexity depend not only on HSC heterogeneity, but also on additional stress conditions. These insights are particularly relevant in the context of stem cell transplantations, which still remain the only curative option for many hematologic diseases, increasingly considered viable for elderly individuals. However, age-related clonal changes post-transplantation are not well understood.

Methods: To address this, we conducted a barcode-based assessment of clonality to investigate post-transplantation changes in both homo- and hetero-chronic settings, combined with low- and high-intensity pre-conditioned recipients.

Results: A robust and polyclonal engraftment was observed across all groups, but with distinct differences in barcode diversity. In particular, transplanted aged HSCs showed no changes in clonality, regardless of recipient age or pre-conditioning. Young HSCs transplanted into severely pre-conditioned old hosts as well as under reduced pre-conditioning, allowed for full lymphoid reconstitution, but showed substantial differences in clonality. Also, myeloid lineage bias, a hallmark of aged HSCs, was confirmed at a clonal level across all experimental groups. Overall, we found that aged HSCs generally maintain clonal diversity similar to young HSCs, but notable differences emerge under hetero-chronic conditions and varying pre-conditioning regimens.

Conclusion: These findings challenge current paradigms and underscore the complex interactions between aging and transplantation conditions.

Importance: Mesenchymal stromal cells (MSCs) possess therapeutic properties that mediate repair. Obesity impairs MSC functionality and therapeutic efficacy, possibly by eliciting dynamic modifications of epigenetic markers, like 5-hydroxymethylcytosine (5hmC).

Objective: We hypothesized that human obesity alters the 5hmC landscape and anti-inflammatory capacity of adipose tissue-derived MSCs to activate the prominent inflammatory signaling mediator Interleukin (IL)-1β.

Design, setting, participants, intervention: Adipose tissue samples were collected from obese and lean individuals (body mass index ≥30 or <30 kg/m2, respectively, n = 11 each) during weight-loss or kidney donation surgery.

Main outcomes and measures: MSCs were harvested and analyzed for 5hmC profiles (MeDIP-seq) and mRNA expression (RNA-seq) (n = 5 each). Subsequently, MSCs or a vehicle were injected into mice, (n = 6 each) and two-weeks later, kidneys were evaluated using in-vivo magnetic resonance imaging and ex vivo studies. The role of IL-1β was then studied in-vitro in MSC-induced immunomodulation using siRNA in macrophages.

Results: Compared to MSC from lean patients, obese-MSC genes showed 2087 differential 5hmC modifications and 175 differential mRNA expression. Among them, 14 genes with overlapping alterations were involved in regulation of cytokine production, prominently IL-1β. Injecting obese MSCs elevated renal expression of IL-1β and M1 macrophage count but lowered kidney perfusion. Silencing IL-1β in obese-MSCs in vitro reduced M1 phenotype switching in co-incubated macrophages.

Conclusions and relevance: Obesity induces epigenetic and gene expression changes in MSCs, particularly in IL-1β, associated with impaired anti-inflammatory functionality of MSCs. Targeting IL-1β could be a useful therapeutic approach to modulate the decline in MSC functionality resulting from obesity.