ABSTRACT Skeletal muscle tissue is highly vascularized, and angiogenesis plays a key role in both muscle homeostasis and regeneration. Despite their importance in regulating various processes within skeletal muscle, little is known about the role of muscle‐resident fibro‐adipogenic progenitors (FAPs) in promoting microvascular angiogenesis. In order to better understand the effects of FAPs on angiogenesis, FAPs were co‐cultured with adipose‐derived microvascular fragments (MVFs) in three‐dimensional fibrin hydrogels. We further tested if pre‐culturing FAPs in brown adipogenic induction media (BAM) influences their ability to promote MVF angiogenesis. MVFs co‐cultured with control FAPs or BAM FAPs for 5 days exhibit robust microvascular network formation with significantly increased vessel percentage area and average vessel length compared to MVFs alone. FAPs cultured in BAM prior to co‐culture with MVFs alter vascular network development compared to MVFs co‐cultured with control FAPs by significantly increasing average vessel length. Collectively, these results indicate that FAPs are key regulators of microvascular angiogenesis and that BAM FAPs have an improved capacity to promote increases in average vessel length. The current findings support the transplantation of FAPs and MVFs and modulation of FAP pro‐angiogenic properties as potential therapeutic approaches for enhancing skeletal muscle angiogenesis in the context of injury and disease.
ABSTRACT The spike (S) protein plays a pivotal role in the invasion of host cells by SARS‐CoV‐2 (COVID‐19). However, the underlying mechanism of spike protein interaction with host cells remains elusive. Here, it was found that human amniotic epithelial stem cells (HuAECs)‐derived exosomes were able to mitigate the cell cycle arrest and lesions of human type II alveolar epithelial primary cells (hAEPC‐II) in vitro induced by SARS‐CoV‐2 S protein. Mechanistically, HuAECs transfered SENP mRNA to hAEPC‐II by releasing exosomes, induced FGF9 protein deSUMOylation and stimulated its expression in hAEPC‐II. Silencing endogenous SENP3 mRNA in HuAECs using siRNA weakens the protective effect of HuAECs‐derived exosomes on hAEPC‐II. Meanwhile, HuAEC‐derived exosomes significantly improved lung tissue damage, inflammatory and fibrosis symptoms of humanized hACE2 KI/KI transgenic mice treated to S protein in vivo. In conclusion, this study reveals a novel mechanism by which HuAECs transfered SENP mRNA to hAEPC‐II by releasing exosomes and attenuate the lesion of hAEPC‐II induced by SARS‐CoV‐2 spike protein.
Silk hydrogels have attracted increasing interest as biocompatible substrates for neural cell culture and regenerative research. Recent research has shown that activation of exchange protein directly activated by cAMP 2 (Epac2) promotes neurite outgrowth in several neuronal models. Here, we investigated the effects of Bombyx mori silk hydrogel, alone or in combination with S-220, a non-hydrolysable cAMP analogue that selectively activates Epac2, on neurite outgrowth. Epac2 activation significantly and dose-dependently enhanced both the total and longest neurite length. Neurons cultured on silk hydrogel alone exhibited neurite outgrowth comparable to control neurons, indicating good biocompatibility of the hydrogel. Addition of S-220 to the culture medium with silk hydrogel modestly improved neurite morphology; however, incorporation of S-220 directly into the hydrogel did not enhance neurite outgrowth but instead reduced neurite length. A subsequently established three-dimensional cortical neuron culture model using silk hydrogel supported neurite extension and increased branching complexity beyond that observed with two-dimensional cultures, despite a shorter overall neurite length. Collectively, these findings support silk hydrogel as a permissive biomaterial substrate for in vitro cortical neuron culture. The system provides a useful platform for investigating neurite outgrowth, neuron-biomaterial interactions and the delivery of bioactive compounds in two- and three-dimensional neural cultures.
Cancer frequently arises from the impaired functioning of the Mitogen-activated protein kinase (MAPK) signaling system, driven by mutation or overexpression of key signaling components. RAF, MEK, ERK, and KRAS inhibitors have significantly improved clinical outcomes, but efficacy is still restricted due to pathway reactivation, adaptive resistance, and signaling cross-talk. These limitations have led to the search for novel therapeutic approaches and molecular targets in the MAPK network. Melanoma, thyroid carcinoma, and pancreatic adenocarcinoma were selected because MAPK pathway alterations contribute to their pathogenesis and influence treatment response. This review examines the biological importance of MAPK signaling in these cancers and discusses MAPK-targeted therapies, mechanisms of resistance, and combination treatment options. It also addresses the expanding evidence on natural compounds that modulate MAPK- related signaling networks and reviews recent transcriptomic findings that have enhanced the identification of clinically relevant molecular targets. Additionally, MAP4K4 has been linked to tumor progression and metastasis, and poor clinical outcomes, indicating its potential as a therapeutic target for future clinical studies. The findings presented in this review suggest that combining transcriptomic evidence with molecular and pharmacological analyses could aid target prioritization and accelerate the development of targeted strategies for MAPK-driven malignancies.
Environmental fluctuations remodel RNA modification landscapes, yet the routes that connect cue detection to writer-eraser-reader control remain dispersed across disciplines. Here, we consolidate upstream mechanisms capable of driving epitranscriptomic change and organize them by response speed. At the fastest proximal level, catalytic output can be modulated through shifts in substrate and cofactor availability, redox and ionic state, temperature, and direct chemical or metal interference with enzyme active sites, although transcriptome-wide RNA readouts may appear later. Over minutes to hours, cue-responsive signaling can reach the machinery through post-translational modification, partner switching, subcellular trafficking, and stress-induced condensates that may gate access to modified transcripts. Across hours to days, regulator abundance and specificity are reshaped by transcriptional programs, translational control, and protein quality-control pathways, enabling adaptation and, in some contexts, persistence. We propose a kinetics-to-sensors approach for interpreting time-resolved epitranscriptomic datasets and prioritizing perturbations that discriminate among candidate upstream inputs. We also outline conceptual gaps and experimental practices needed to establish causal cue-to-mark chains.
