npj Regenerative Medicine最新文献

The acute loss of critical skeletal muscle volume or volumetric muscle loss (VML) results in persistent inflammation, fibrotic scarring, permanent strength deficits and long-term disability. The molecular mechanisms that drive fibrosis following VML injury have primarily been evaluated in rodent models, however, translation of these findings to large animals remains underexplored. Herein, we utilized a canine model of VML and a mesoscopic approach to evaluate how treatment with an extracellular matrix hydrogel impacts the early cellular circuitry regulating inflammation, fibrosis and muscle regeneration. We observed treatment with extracellular matrix dampens inflammation and fibrosis by spatially confining the immune reaction to the superficial surface of the wound. Simultaneously, extracellular matrix treatment improved muscle stem cell and regenerative progenitor infiltration into the VML defect and limited degeneration of intact myofibers. These results establish a spatially informed framework for understanding how extracellular matrix hydrogel treatment impacts regenerative trajectories and cellular communities post-VML.

Renal failure due to drug nephrotoxicity or disease is frequently observed in patients. The development of in vitro models able to recapitulate kidney biology offers new possibilities to study drug toxicity or model diseases. Induced pluripotent stem cell-derived kidney organoids already show promise, but several drawbacks must be overcome to maintain them in culture, among which is the presence of non-renal cell populations such as cartilage. We modified the culture protocol and maintained kidney organoids in medium containing FGF9 for 1 additional week compared to the control protocol (Takasato). In comparison to the control, the FGF9-treated kidney organoids had reduced cartilage at day 7 + 25 and diminished chondrocyte marker expression. Importantly, the renal structures assessed by immunofluorescence were unaffected by the FGF9 treatment. This reduction of cartilage produces a higher quality kidney organoid that can be maintained longer in culture to improve their maturation for further in vivo work.

The key to surviving severe burns is rapid burn wound excision and closure, yet extensive wounds often surpass natural healing capacity. Alternative treatments, such as synthetic skin substitutes, have not emerged as a standard, optimal solution. Stem cell therapies, especially using allogenic sources, show promise in enhancing wound repair. Induced mesenchymal stem cells (iMSCs) have demonstrated vast possibilities to overcome traditional stem cell therapy limitations. This study utilized Cord tissue-derived iMSCs (CT-iMSCs) incorporated into well-established epidermal-dermal substitutes Integra® Dermal Regeneration Template (DRT) at 5000-20,000 cells/cm² in a porcine full-thickness burn model to test their regenerative capabilities. We evaluated healing outcomes, inflammation, neovascularization, collagen levels, and fibrosis markers. Wounds treated with CT-iMSCs showed notable improvements, including faster wound healing, better epithelialization, and marked improvements in healing markers compared to controls. These data support the potential of iMSCs as an ideal cell source for autologous skin regeneration.

Epithelial tissue integrity is maintained through specialized intercellular junctions known to coordinate homeostatic processes. In this context, outside-in signaling and mechanotransduction through desmosomal cadherins, the building blocks of desmosomes and main stress bearers in epithelial tissue, are only starting to emerge. To better understand the dual function of desmosomal cadherins in structural integrity and cellular signaling, we here performed a systematic, unbiased review on pathogenic signaling effectors identified in models and patients with pemphigus vulgaris (PV). PV is an autoimmune blistering disorder characterized by disruption of desmosomal transadhesion through autoantibodies mainly targeting the desmosomal cadherins desmoglein (Dsg) 3 or Dsg1 and Dsg3. The survey of functionally validated pathogenic pathways published since inception in 1977 up to mid-2024 identifies 128 studies and 128 signaling molecules, highlighting a coherent network of biomechanical, bioelectrical, and biochemical signaling events. This in-depth analysis will stimulate future research as well as development of potential therapeutic applications beyond PV.

It is widely acknowledged that articular cartilage lacks the ability to regenerate. However, if such regeneration were possible, which cell type would generate new tissue? The p21^-/- mouse provides an excellent platform to explore this question, hence, we conducted lineage tracing on Paired related homeobox 1 (Prrx1/Prx1) cells post-injury to determine whether endogenous Prx1⁺ cells contribute to regenerated tissues post-injury. p21^-/- mice displayed enhanced endogenous cartilage regeneration, accompanied by notable differences in the number and kinetics of Prx1⁺ cells within and around the injury site. In p21^-/- mice, Prx1⁺ cells underwent chondrogenesis, ultimately contributing to the regenerated articular cartilage layer. These findings underscore the impact of tissue-resident cells on cartilage regeneration, albeit under abnormal conditions. If the conditions within the joint could be manipulated to favor such a regenerative environment, these endogenous cell types might be recruited to facilitate the formation of a new articular cartilage surface post-injury.

Peptide-based supramolecular nanostructures offer a versatile platform with substantial promise for clinical translation in regenerative medicine. These systems allow for the incorporation of biologically active sequences and can be engineered to modulate tissue-specific parameters such as stiffness, diffusivity, and biodegradability. We developed here a bioactive supramolecular nanostructure containing a peptide designed based on glial cell-derived neurotrophic factor. These nanostructures form scaffolds that mimic important trophic effects provided by this growth factor on iPSC-derived human dopaminergic neurons. Our in vitro data show that the nanostructures promote cell viability, confer neuroprotection against 6-hydroxydopamine toxicity, enhance neuronal morphology, facilitate electrophysiological maturation, and induce genes involved in neuronal survival. We also found that the scaffold promoted axonal extension in midbrain human organoids. These findings suggest that the supramolecular system could be useful to improve outcomes in cell-based therapies for Parkinson's disease, where progressive dopaminergic degeneration is a hallmark.

Tissue and organ regeneration are common among aquatic invertebrates, yet these taxa and their potential as model organisms remain underexplored. We present evidence of extensive regenerative capabilities in aquatic invertebrates, highlighting examples of whole-body regeneration (WBR), a peak form of regeneration, where entire organisms regenerate from minute body fragments. Among the many examples of WBR, we focus on botryllid ascidians, an intriguing group of invertebrate chordates that display chordate tissue complexity while demonstrating WBR from small fragments of blood vessels. Centering on WBR in the model species Botrylloides leachi, we outline shared characteristics of WBR across botryllid ascidians including the presence of circulating multipotent stem cells, systemic induction processes, and ensuing competition among regeneration sites, culminating in the restoration of a complete organism. This regeneration mode is distinct from those in mammals and humans. Further research may offer valuable insights into mechanisms by which tissue fragments reinstate new organisms.

Premature ovarian failure (POF) is a disease closely related to the apoptosis of granulosa cells (GCs) in the follicle. In this study, exogenous melatonin (Mel) was used to interfere with POF model mice, so as to provide reference for Mel prevention and treatment of POF. Mel could promote estrogen secretion and improve ovarian physiological function in mice. In GCs, mitochondrial membrane potential increases and ATP content increases, LC3/LC3-LL and Beclin1 expression increases, p62 expression decreases, which promoted the occurrence of autophagy. Intersecting target screening, GO and KEGG enrichment analysis of Mel and POF revealed that estrogen receptor 1 (ESR1) was the most compatible target for Mel action; meanwhile, Mel had a high enrichment value in the PI3K-AKT-mTOR pathway. It was detected that Mel could increase the expression of ESR1 and inhibit the phosphorylation levels of PI3K, AKT, and mTOR to promote autophagy and reduce apoptosis of GCs.

The success of implanted tissue-engineered vascular grafts (TEVGs) relies on the coordinated inflammation and wound healing processes that simultaneously degrade the scaffold and guide the formation of a neovessel. Dysregulated responses can lead to aberrant remodeling (e.g., stenosis), impacting the long-term outcome and functionality of the TEVG. We developed a TEVG that, despite demonstrating growth capacity in the clinic, exhibited an unexpectedly high incidence of stenosis, or narrowing of the graft lumen. This study identified platelet-mediated immune signaling via the lysosomal trafficking regulator (Lyst) as a key driver of stenosis. Lyst mutations significantly impaired platelet dense granule exocytosis yet preserved alpha granule secretion and adhesion to the biomaterial. Uncontrolled platelet aggregation, potentiated by dense granule signaling, results in the formation of a mural thrombus that remodels into occlusive neotissue. Importantly, inhibiting sustained platelet aggregation using the P2Y12 antagonist, prasugrel, is a successful strategy for optimizing neotissue formation and improving overall TEVG performance.

Following bone injury, macrophages (Mφ) initiate the immune response by secreting signals that recruit mesenchymal stem cells (MSC) and other niche cells to shape healing. Despite its importance, the potential of enhancing bone regeneration by modulating immune-stem cell crosstalk is largely unexplored. Here, we report a macroporous microribbon (µRB) scaffold with tunable ratios of gelatin (Gel) and chondroitin sulfate (CS), achieving rapid endogenous bone regeneration in a critical-sized defect model without exogenous growth factors or cells. The 3D MSC/Mφ co-culture model, but not the mono-culture model, effectively identified Gel50_CS50 as the leading ratio for accelerating bone regeneration in vivo. Single-cell sequencing (scRNAseq) and CellChat analysis revealed that Gel50_CS50 significantly enhanced the cellular crosstalk among Mφ and other bone niche cell types, with signaling pathways linked to anti-inflammation, angiogenesis, and osteogenesis. This study demonstrates Gel50_CS50 µRB as a promising biomaterial-based therapy for treating critical-sized bone defects by modulating cellular crosstalk.