Cellular rejuvenation:molecular mechanisms and potential therapeutic interventions for diseases

The ageing process is a systemic decline from cellular dysfunction to organ degeneration,with more predisposition to deteriorated disorders.Rejuvenation refers to giving aged cells or organisms more youthful characteristics through various techniques,such as cellular reprogramming and epigenetic regulation.The great leaps in cellular rejuvenation prove that ageing is not a one-way street,and many rejuvenative interventions have emerged to delay and even reverse the ageing process.Defining the mechanism by which roadblocks and signaling inputs influence complex ageing programs is essential for understanding and developing rejuvenative strategies.Here,we discuss the intrinsic and extrinsic factors that counteract cell rejuvenation,and the targeted cells and core mechanisms involved in this process.Then,we critically summarize the latest advances in state-of-art strategies of cellular rejuvenation.Various rejuvenation methods also provide insights for treating specific ageing-related diseases,including cellular reprogramming,the removal of senescence cells(SCs)and suppression of senescence-associated secretory phenotype(SASP),metabolic manipulation,stem cells-associated therapy,dietary restriction,immune rejuvenation and heterochronic transplantation,etc.The potential applications of rejuvenation therapy also extend to cancer treatment.Finally,we analyze in detail the therapeutic opportunities and challenges of rejuvenation technology.Deciphering rejuvenation interventions will provide further insights into anti-ageing and ageing-related disease treatment in clinical settings.

A volar skin excisional wound model for in situ evaluation of multiple-appendage regeneration and innervation

Background:Promoting rapid wound healing with functional recovery of all skin appendages is the main goal of regenerative medicine.So far current methodologies,including the commonly used back excisional wound model(BEWM)and paw skin scald wound model,are focused on assessing the regeneration of either hair follicles(HFs)or sweat glands(SwGs).How to achieve de novo appendage regeneration by synchronized evaluation of HFs,SwGs and sebaceous glands(SeGs)is still challenging.Here,we developed a volar skin excisional wound model(VEWM)that is suitable for examining cutaneous wound healing with multiple-appendage restoration,as well as innervation,providing a new research paradigm for the perfect regeneration of skin wounds.Methods:Macroscopic observation,iodine-starch test,morphological staining and qRT-PCR anal-ysis were used to detect the existence of HFs,SwGs,SeGs and distribution of nerve fibres in the volar skin.Wound healing process monitoring,HE/Masson staining,fractal analysis and behavioral response assessment were performed to verify that VEWM could mimic the pathological process and outcomes of human scar formation and sensory function impairment.Results:HFs are limited to the inter-footpads.SwGs are densely distributed in the footpads,scattered in the IFPs.The volar skin is richly innervated.The wound area of the VEWM at 1,3,7 and 10 days after the operation is respectively 89.17%±2.52%,71.72%±3.79%,55.09%±4.94%and 35.74%±4.05%,and the final scar area accounts for 47.80%±6.22%of the initial wound.While the wound area of BEWM at 1,3,7 and 10 days after the operation are respectively 61.94%±5.34%,51.26%±4.89%,12.63%±2.86%and 6.14%±2.84%,and the final scar area accounts for 4.33%±2.67%of the initial wound.Fractal analysis of the post-traumatic repair site for VEWM vs human was performed:lacunarity values,0.040±0.012 vs 0.038±0.014;fractal dimen-sion values,1.870±0.237 vs 1.903±0.163.Sensory nerve function of normal skin vs post-traumatic repair site was assessed:mechanical threshold,1.05±0.52 vs 4.90 g±0.80;response rate to pin-prick,100%vs 71.67%±19.92%,and temperature threshold,50.34◦C±3.11◦C vs 52.13◦C±3.54◦C.Conclusions:VEWM closely reflects the pathological features of human wound healing and can be applied for skin multiple-appendages regeneration and innervation evaluation.