- The activation of redox-sensitive transcription factor Nrf2 1) curbs oxidative damage, 2) preserves vital immune functions (including inflammatory migration), 3) delays the acquisition of senescence-like features.
- Macrophage Nrf2 also acts non-autonomously to limit ROS-induced collateral damage to surrounding tissues
- Microglia are not necessary for the initial process of myelin ensheathment during development.
- However, microglia play a crucial role in regulating myelin growth and associated cognitive function after development.
- Microglia are also responsible for maintaining myelin integrity and preventing its degeneration.
- The absence of microglia leads to the emergence of a myelinating oligodendrocyte state with altered lipid metabolism, contributing to the loss of myelin health.
- This mechanism is regulated through the disruption of the TGFβ1-TGFβR1 axis.
- Targeting microglia could be a potential therapeutic approach for conditions characterized by dysregulated myelin growth and integrity, such as ageing and neurodegenerative diseases.
Cell Secretome vs Stem Cells
- Stem cell-based therapies were initially explored for tissue regeneration and immunomodulation.
- Engraftment and differentiation of stem cells were thought to be the main mechanisms.
- However, poor homing and engraftment of systemically and topically applied stem cells, leading to a search for alternative mechanisms of action
- Non-stem cells, particularly autologous activated blood mononuclear cells, showed improvement in wound healing.
- Stem cells release cytoprotective, trophic, and immunomodulatory paracrine factors. The sum of these factors is termed the cell secretome, which has become a major focus of recent studies.
- Proteins, lipids, and extracellular vesicles (EVs) are the major fractions of cell secretomes.
- EVs, including exosomes and microvesicles, are extensively researched and mediate bioactive properties through membrane interactions and cargo delivery.
- The scope of potential indications for secretome-based therapeutics extends the treatment of chronic wounds because the tissue-regenerative properties of these candidates have been documented in almost all organ systems (Beer et al., 2016;Moghadasi et al., 2021
https://www.jidonline.org/article/S0022-202X(23)00162-8/fulltext
Cellular senescence has typically been associated with negative effects, but in a new study, it is shown to enhance newt limb regeneration.
- Salamanders can regenerate their entire limbs throughout their lifespan.
- Limb regeneration involves significant modulation of cellular plasticity.
- The process of limb regeneration induces cellular senescence, which is irreversible cell cycle arrest.
- Exogenously derived senescent cells promote dedifferentiation of mature muscle tissue that generates regenerative progenitors.
- Senescent cells promote myotube cell cycle re-entry and reversal of muscle identity through secreted factors.
- The FGF-ERK signaling axis is identified as a critical mediator of senescence-induced muscle dedifferentiation.
- Cellular senescence plays a beneficial role as a modulator of dedifferentiation, which is crucial for the regeneration of complex structures.
- Niche signals and stem cell maintenance:
- Niche signals have two roles: maintaining stem cells in prolonged quiescence or transiently activating them for proper regeneration.
- Altering balanced niche signaling can result in regenerative disorders.
- Relationship between melanocytic skin nevi and hair growth:
- Melanocytic skin nevi in humans often exhibit excessive hair growth, suggesting hair stem cell hyperactivity.
- Study using genetic mouse models of nevi:
- Dermal clusters of senescent melanocytes in nevi induce changes in epithelial hair stem cells.
- Senescent melanocytes drive hair stem cells to exit quiescence and alter their transcriptome and composition.
- These changes significantly enhance hair renewal.
- Identification of nevus secretome and its role in hair growth:
- Nevus melanocytes activate a distinct secretome enriched with signaling factors.
- Osteopontin, a prominent signaling factor in nevi, plays a crucial role in inducing hair growth.
- Injection of osteopontin or its genetic overexpression is sufficient to induce robust hair growth in mice.
- Germline and conditional deletions of osteopontin or its receptor CD44 prevent enhanced hair growth induced by dermal nevus melanocytes.
- Osteopontin is overexpressed in human hairy nevi and stimulates new growth of human hair follicles.
- Senescent cell clusters as a therapeutic target in regenerative disorders:
- Accumulation of senescent cells generally hampers tissue regeneration.
- However, the study reveals that senescent cell clusters and their secretome can enhance adjacent intact stem cell activity and stimulate tissue renewal.
- This finding highlights senescent cells and their secretome as potential therapeutic targets in regenerative disorders.
Signalling by senescent melanocytes hyperactivates hair growth | Nature
New study:
- Senescent cells as mediators of cellular plasticity: The study reveals that senescent cells emit signals that can destabilize neighboring somatic cells, leading to their reprogramming into stem cells. This reprogramming plays a pivotal role in driving whole-body regeneration in the cnidarian Hydractinia symbiolongicarpus.
- Prevention of reprogramming and regeneration through inhibition of senescence: The researchers found that inhibiting senescence, either through pharmacological or genetic means, prevents the reprogramming of somatic cells and hinders the process of regeneration.
- Induction of senescence for enhanced regeneration: Interestingly, the induction of transient ectopic senescence in a regenerative context resulted in the formation of extra stem cells and accelerated the regeneration process. This suggests that senescence signaling can be manipulated to promote cellular plasticity and enhance regeneration.
- Implications for understanding ancient mechanisms of cellular plasticity: The study proposes that senescence signaling is an ancient mechanism that mediates cellular plasticity. By gaining a deeper understanding of the senescence environment that promotes cellular reprogramming, researchers may uncover new strategies to enhance regeneration in complex animals.
- Genetically immortalized bovine satellite cells (iBSCs) achieved over 120 doublings at the time of publication.
- The goal is to produce millions of metric tons of biomass annually through in vitro expansion of muscle cells from food-relevant species.
- Genetically immortalized cells offer rapid growth and escape from cellular senescence.
- The development involves constitutive expression of bovine Telomerase reverse transcriptase (TERT) and Cyclin-dependent kinase 4 (CDK4) in iBSCs.
- The genetically immortalized cells maintain their capacity for myogenic differentiation.
Immortalized Bovine Satellite Cells for Cultured Meat Applications | ACS Synthetic Biology
Pharmacological YAP activation promotes regenerative repair of cutaneous wounds
- Life Expectancy Impact: Chronic cutaneous wounds are associated with a decrease in life expectancy.
- Quality of Life Impact: Chronic cutaneous wounds also negatively affect the quality of life of affected individuals.
- Efficacy in Animal Models: The topical application of PY-60, a small-molecule activator of YAP, promoted regenerative repair of cutaneous wounds in pig models.
- Efficacy in Human Models: The topical application of PY-60 also promoted regenerative repair of cutaneous wounds in human models.
- Proliferative Transcriptional Program: Pharmacological YAP activation induces a reversible pro-proliferative transcriptional program in keratinocytes and dermal cells.
- Accelerated Healing: The pro-proliferative transcriptional program results in accelerated re-epithelization and regranulation of the wound bed.
- Generalizable Therapeutic Approach: Transient topical administration of a YAP activating agent shows potential as a generalizable therapeutic approach for treating cutaneous wounds.
- MBTD1 is highly expressed in fetal hematopoietic stem cells (HSCs).
- Numbers of HSCs and progenitors increase in Mbtd1-deficient hematopoietic tissues.
- Mbtd1-deficient HSCs exhibit hyperactive cell cycle.
- MBTD1 directly binds to the promoter region of FoxO3a.
- FOXO3a is a forkhead protein essential for HSC quiescence.
- MBTD1 interacts with components of the TIP60 chromatin remodeling complex.
- MBTD1 interacts with proteins involved in HSC and other stem cell functions.
- Restoration of FOXO3a activity in Mbtd1-deficient HSCs rescued cell cycle and pool size abnormalities.
- A study assessed the impact of aging on the cardiac neurovascular interface, where nerves align with blood vessels.
- Aging leads to a reduction in nerve density within the ventricle of the heart.
- Aging also dysregulates genes related to neuroregulation derived from blood vessels.
- The aging process down-regulates microRNA 145 (miR-145) and leads to the derepression of the neurorepulsive factor semaphorin-3A (Sema3A).
- Deletion of miR-145 or overexpression of endothelial Sema3A reduces axon density, mimicking the phenotype of an aged heart.
- Senescent cells accumulate with age and are associated with a decline in nerve density in the heart.
- Removing senescent cells rescues age-induced denervation, reverses Sema3A expression, preserves heart rate patterns, and reduces electrical instability.
- These findings suggest that senescence-mediated regulation of nerve density plays a role in age-associated cardiac dysfunction.
- The periodontium, a complex structure, is composed of interconnected soft and mineralized tissues.
- Silicon and lithium stimulate bone repair via silicic acid release and activate the Wnt/β-catenin pathway.
- Existing materials for combined lithium and silicon release have limited control over ion release amounts and kinetics.
- Porous silicon provides controlled silicic acid release, inducing osteogenesis for bone regeneration.
Prelithiation, a strategy for battery technology, introduces controllable amounts of lithium within porous silicon. - The study introduces lithiated porous silicon nanowires (LipSiNs) as a biocompatible and bioresorbable material.
- LipSiNs incorporate lithium to between 1% and 40% of silicon content.
- LipSiNs release lithium and silicic acid in a tailorable fashion from days to weeks.
- LipSiNs combine osteogenic, cementogenic, and Wnt/β-catenin stimuli to regenerate bone, cementum, and periodontal ligament fibers in a murine periodontal defect.
- Gut and liver communication occurs through various pathways: biliary tract, portal vein, and systemic circulation.
- Liver-derived pigment epithelium-derived factor (PEDF) regulates intestinal stem cell (ISC) hyperproliferation.
- PEDF acts as a soluble Wnt inhibitor, restraining the Wnt/β-catenin signaling pathway to maintain gut homeostasis.
- Intestinal inflammation triggers microbial danger signals sensed by the liver, leading to repression of PEDF production via peroxisome proliferator-activated receptor-α (PPARα).
- Repression of PEDF liberates ISC proliferation, accelerating gut tissue repair.
- Treatment with fenofibrate, a PPARα agonist, enhances colitis susceptibility due to increased PEDF activity.
- Accumulation of senescent cells in tissues contributes to aging and age-related diseases.
- Botanical extracts, rich in phytoconstituents, are potential sources for therapies targeting senescence to improve healthspan.
- Daily oral administration of a standardized extract of Salvia haenkei (Haenkenium, HK) extended both lifespan and healthspan in naturally aged mice.
- HK treatment inhibited age-induced inflammation, fibrosis, and senescence markers across various tissues and increased muscle strength and fur thickness.
- HK treatment also reduced acutely induced senescence by the chemotherapeutic agent doxorubicin, as observed in p16LUC reporter mice.
- Mass spectrometry identified luteolin as the most concentrated flavonoid in HK, acting as a senomorphic compound.
- Luteolin was found to disrupt the p16–CDK6 interaction, which may underlie the longevity-promoting effects of HK.
- The study demonstrates that HK promotes longevity in mice, potentially by modulating cellular senescence and disrupting the p16–CDK6 interaction.
- mRNA would be degraded prematurely without molecular caps protecting the two mRNA ends, for instance, the 3’ end mRNA is equipped with a polyadenine tail with an average length of 200 nucleotides. But even this shield does not last long as deadenylation occurs – the average half-life of mRNA is only 7 hours.
- Deadenylation is a process that the target mRNA is recruited by RNA-binding proteins to the protein complex CCR4-NOT, which removes one adenine after the other.
- The subunit NOT9 binds various RNA binding proteins which recruit mRNA in a sequence-specific manner to the CCR4-NOT complex to promote their deadenylation.
- the hydrocarbon stapled peptide NIP-2 (KD = 60.4 nM) was able to inhibit RNA-binding (IC 50 = 333nM) as well as the deadenylation activity of the CCR4-NOT complex in vitro while being cell-permeable (EC 50 = 2.44 μM).
- NIP-2 bound to NOT9 allowed further optimization of thepeptide through point mutation leading to NIP-2-H27A-N 3 (KD = 122nM) with high cell permeability (cell-permeability EC 50 = 0.34 μM).
- The optimized peptide was able to inhibit deadenylation of target mRNAs when used in HeLa cells at a concentration of 100 μM demonstrating the feasibility of increasing mRNA stability.
- This new strategy provides us to extend the lifespan of mRNA by protecting it from its dismantling.
ARTICLE: Stapled Peptides as Inhibitors of mRNA Deadenylation
https://onlinelibrary.wiley.com/doi/epdf/10.1002/anie.202413911
- Calorie restriction (CR) is a potential intervention to slow aging.
- CR reduced circulating biomarkers of cellular senescence.
- CR improved metabolic health, as indicated by changes in HOMA-IR and insulin sensitivity.
- CR reduced senescence-related gene expression in adipose tissue.
Aging Cell 2024 Feb;23(2):e14038. doi: 10.1111/acel.14038. Epub 2023 Nov 14.
Synthetic peptides, combined with patient blood, can revolutionize personalized regenerative medicine by mimicking the body’s natural healing process.