Implanting mechanically reprogrammed fibroblasts for aged tissue regeneration and wound healing.

Cell-based therapies are essential for tissue regeneration and wound healing during aging. Autologous transplantation of aging cells is ineffective due to their increased senescence and reduced tissue remodeling capabilities. Alternatively, implanting reprogrammed aged cells provides unique opportunities. In this paper, we demonstrate the implantation of partially reprogrammed aged human dermal fibroblasts into in vitro aged skin models for tissue regeneration and wound healing. The partially reprogrammed cells were obtained using our previously reported, highly efficient mechanical approach. Implanted cells showed enhanced expression of extracellular matrix proteins in the large area of aged tissue. In addition, the implanted cells at wound sites showed increased extracellular matrix protein synthesis and matrix alignment. Transcriptome analysis, combined with chromatin biomarkers, revealed these implanted cells upregulated tissue regeneration and wound healing pathways. Collectively our results provide a novel, nongenetic, partial reprogramming of aged cells for cell-based therapies in regenerative medicine.

Detecting radio- and chemoresistant cells in 3D cancer co-cultures using chromatin biomarkers.

The heterogenous treatment response of tumor cells limits the effectiveness of cancer therapy. While this heterogeneity has been linked to cell-to-cell variability within the complex tumor microenvironment, a quantitative biomarker that identifies and characterizes treatment-resistant cell populations is still missing. Herein, we use chromatin organization as a cost-efficient readout of the cells' states to identify subpopulations that exhibit distinct responses to radiotherapy. To this end, we developed a 3D co-culture model of cancer spheroids and patient-derived fibroblasts treated with radiotherapy. Using the model we identified treatment-resistant cells that bypassed DNA damage checkpoints and exhibited an aggressive growth phenotype. Importantly, these cells featured more condensed chromatin which primed them for treatment evasion, as inhibiting chromatin condensation and DNA damage repair mechanisms improved the efficacy of not only radio- but also chemotherapy. Collectively, our work shows the potential of using chromatin organization to cost-effectively study the heterogeneous treatment susceptibility of cells and guide therapeutic design.

Ferritin-mediated iron detoxification promotes hypothermia survival in Caenorhabditis elegans and murine neurons.

How animals rewire cellular programs to survive cold is a fascinating problem with potential biomedical implications, ranging from emergency medicine to space travel. Studying a hibernation-like response in the free-living nematode Caenorhabditis elegans, we uncovered a regulatory axis that enhances the natural resistance of nematodes to severe cold. This axis involves conserved transcription factors, DAF-16/FoxO and PQM-1, which jointly promote cold survival by upregulating FTN-1, a protein related to mammalian ferritin heavy chain (FTH1). Moreover, we show that inducing expression of FTH1 also promotes cold survival of mammalian neurons, a cell type particularly sensitive to deterioration in hypothermia. Our findings in both animals and cells suggest that FTN-1/FTH1 facilitates cold survival by detoxifying ROS-generating iron species. We finally show that mimicking the effects of FTN-1/FTH1 with drugs protects neurons from cold-induced degeneration, opening a potential avenue to improved treatments of hypothermia.

End-of-life targeted degradation of DAF-2 insulin/IGF-1 receptor promotes longevity free from growth-related pathologies.

Preferably, lifespan-extending therapies should work when applied late in life without causing undesired pathologies. Reducing insulin/insulin-like growth factor (IGF)-1 signaling (IIS) increases lifespan across species, but the effects of reduced IIS interventions in extreme geriatric ages remains unknown. Using the nematode Caenorhabditis elegans, we engineered the conditional depletion of the DAF-2/insulin/IGF-1 transmembrane receptor using an auxin-inducible degradation (AID) system. This allowed for the temporal and spatial reduction in DAF-2 protein levels at time points after which interventions such as RNAi become ineffective. Using this system, we found that AID-mediated depletion of DAF-2 protein surpasses the longevity of daf-2 mutants. Depletion of DAF-2 during early adulthood resulted in multiple adverse phenotypes, including growth retardation, germline shrinkage, egg retention, and reduced brood size. By contrast, AID-mediated depletion of DAF-2 post-reproduction, or specifically in the intestine in early adulthood, resulted in an extension of lifespan without these deleterious effects. Strikingly, at geriatric ages, when 75% of the population had died, AID-mediated depletion of DAF-2 protein resulted in a doubling in lifespan. Thus, we provide a proof-of-concept that even close to the end of an individual's lifespan, it is possible to slow aging and promote longevity.

The goal of geroscience, or research into old age, is to promote health during old age, and thus, to increase lifespan. In the body, the groups of biochemical reactions, or 'pathways', that allow an organism to sense nutrients, and regulate growth and stress, play major roles in ensuring healthy aging. Indeed, organisms that do not produce a working version of the insulin/IGF-1 receptor, a protein involved in one such pathway, show increased lifespan. In the worm Caenorhabditis elegans, mutations in the insulin/IGF-1 receptor can even double their lifespan. However, it is unclear whether this increase can be achieved once the organism has reached old age. To answer this question, Venz et al. genetically engineered the nematode worm C. elegans so that they could trigger the rapid degradation of the insulin/IGF-1 receptor either in the entire organism or in a specific tissue. Venz et al. started by aging several C. elegans worms for three weeks, until about 75% had died. At this point, they triggered the degradation of the insulin/IGF-1 receptor in some of the remaining worms, keeping the rest untreated as a control for the experiment. The results showed that the untreated worms died within a few days, while worms in which the insulin/IGF-1 receptor had been degraded lived for almost one more month. This demonstrates that it is possible to double the lifespan of an organism at the very end of life. Venz et al.'s findings suggest that it is possible to make interventions to extend an organism's lifespan near the end of life that are as effective as if they were performed when the organism was younger. This sparks new questions regarding the quality of this lifespan extension: do the worms become younger with the intervention, or is aging simply slowed down?