Autophagy critically controls skin inflammation and apoptosis-induced stem cell activation.

Macroautophagy/autophagy is a cellular recycling program regulating cell survival and controlling inflammatory responses in a context-dependent manner. Here, we demonstrate that keratinocyte-selective ablation of Atg16l1, an essential autophagy mediator, results in exacerbated inflammatory and neoplastic skin responses. In addition, mice lacking keratinocyte autophagy exhibit precocious onset of hair follicle growth, indicating altered activation kinetics of hair follicle stem cells (HFSCs). These HFSCs also exhibit expanded potencies in an autophagy-deficient context as shown by de novo hair follicle formation and improved healing of abrasion wounds. ATG16L1-deficient keratinocytes are markedly sensitized to apoptosis. Compound deletion of RIPK3-dependent necroptotic and CASP8-dependent apoptotic responses or of TNFRSF1A/TNFR1 reveals that the enhanced sensitivity of autophagy-deficient keratinocytes to TNF-dependent cell death is driving altered activation of HFSCs. Together, our data demonstrate that keratinocyte autophagy dampens skin inflammation and tumorigenesis but curtails HFSC activation by restraining apoptotic responses.Abbreviations: ATG16L1: autophagy related 16 like 1; DMBA: 2,4-dimethoxybenzaldehyde; DP: dermal papilla; EpdSCs: epidermal stem cells; Gas6: growth arrest specific 6; HF: hair follicle; HFSC: hair follicle stem cell; IFE: interfollicular epidermis; KRT5: keratin 5; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; PMK: primary mouse keratinocyte; RIPK3: receptor-interacting serine-threonine kinase 3; scRNAseq: single-cell RNA-sequencing; SG: sebaceous gland; TEWL: transepidermal water loss; TPA: 12-O-tetradecanoylphorbol-13-acetate; TNF: tumor necrosis factor; TNFRSF1A/TNFR1: tumor necrosis factor receptor superfamily, member 1a; UMAP: uniform manifold approximation and projection.

A Systematic Review on Extracellular Vesicles-Enriched Fat Grafting: A Shifting Paradigm.

BACKGROUND: Recent evidence confirms that mesenchymal stem cells (MSCs) facilitate angiogenesis mainly through paracrine function. Extracellular vesicles (EVs) are regarded as key components of the cell secretome, possessing functional properties of their source cells. Subsequently, MSC-EVs have emerged as a novel cell-free approach to improve fat graft retention rate. OBJECTIVES: The authors sought to provide a systematic review of all studies reporting the utilization of MSC-EVs to improve graft retention rate. METHODS: A systematic search was undertaken employing the Embase, PubMed, and Cochrane Central Register of Controlled Trials databases. Outcome measures included donor/receptor organism of the fat graft, study model, intervention groups, evaluation intervals, EV research data, and in vitro and in vivo results. RESULTS: Of the total 1717 articles, 62 full texts were screened. Seven studies reporting on 294 mice were included. Overall, EV-treated groups showed higher graft retention rates compared with untreated groups. Notably, retention rate was similar following EV and MSC treatment. In addition to reduced inflammation, graft enrichment with EVs resulted in early revascularization and better graft integrity. Interestingly, hypoxic preconditioning of MSCs improved their beneficial paracrine effects and led to a more proangiogenic EV population, as observed by both in vitro and in vivo results. CONCLUSIONS: MSC-EVs appear to offer an interesting cell-free alternative to improve fat graft survival. Although their clinical relevance remains to be determined, it is clear that not the cells but rather their secretome is essential for graft survival. Thus, a paradigm shift from cell-assisted lipotransfer towards "secretome-assisted lipotransfer" is well on its way.

Expanding Clinical Indications of Mechanically Isolated Stromal Vascular Fraction: A Systematic Review.

BACKGROUND: Mechanically isolated stromal vascular fraction (tSVF, tissue SVF) is a potent regenerative solution, increasingly used as a therapeutic modality for a variety of pathologies. With recent evidence conclusively favoring mechanical isolation over enzymatic alternatives, the therapeutic share and indications of tSVF are expected to grow even further. OBJECTIVES: The aim of this study was to provide a systematic review of all studies reporting on the use of tSVF. METHODS: A systematic search was undertaken of the Embase, PubMed, Web of Science, and Cochrane Central Register of Controlled Trials databases. Outcome measures included clinical indications, such as recipient area, adverse events, clinical results recipient area, method of application, follow-up duration and evaluation methods. RESULTS: Of the total of 4505 articles identified, 186 full-texts were screened. Thirty-four studies, reporting on 1443 patients were included. tSVF-based therapy was observed for 10 different pathologies, including aged skin (8 studies), scars (5), wounds (6), osteoarthritis (6), tendinopathy (2), temporomandibular joint disorders (1), androgenic alopecia (1), perianal fistula (3), migraine (1), and vocal fold scarring (1). Across all studies, tSVF-based therapy resulted in favorable clinical results. Overall, 50 (3.43%) minor and one (0.07%) major adverse events were observed, mainly related to the liposuction procedure. CONCLUSIONS: tSVF offers a safe, easy and legal treatment modality for a range of indications. Future research is indicated to identify the optimal isolation protocol, dose and timing. In addition, basic research remains crucial to identify the mechanism of action of SVF within different pathologies.

Surgical treatment of stage IV colorectal cancer with synchronous liver metastases: A systematic review and network meta-analysis.

BACKGROUND: The ideal treatment approach for colorectal cancer (CRC) with synchronous liver metastases (SCRLM) remains debated. We performed a network meta-analysis (NMA) comparing the 'bowel-first' approach (BFA), simultaneous resection (SIM), and the 'liver-first' approach (LFA). METHODS: A systematic search of comparative studies in CRC with SCRLM was undertaken using the Embase, PubMed, Web of Science, and CENTRAL databases. Outcome measures included postoperative complications, 30- and 90-day mortality, chemotherapy use, treatment completion rate, 3- and 5-year recurrence-free survival, and 3- and 5-year overall survival (OS). Pairwise and network meta-analysis were performed to compare strategies. Heterogeneity was assessed using the Higgins I2 statistic. RESULTS: One prospective and 43 retrospective studies reporting on 10 848 patients were included. Patients undergoing the LFA were more likely to have rectal primaries and a higher metastatic load. The SIM approach resulted in a higher risk of major morbidity and 30-day mortality. Compared to the BFA, the LFA more frequently resulted in failure to complete treatment as planned (34% versus 6%). Pairwise and network meta-analysis showed a similar 5-year OS between LFA and BFA and a more favorable 5-year OS after SIM compared to LFA (odds ratio 0.25-0.90, p = 0.02, I2 = 0%), but not compared to BFA. CONCLUSION: Despite a higher tumor load in LFA compared to BFA patients, survival was similar. A lower rate of treatment completion was observed with LFA. Uncertainty remains substantial due to imprecise estimates of treatment effects. In the absence of prospective trials, treatment of stage IV CRC patients should be individually tailored.

Effect of treatment sequence on survival in stage IV rectal cancer with synchronous and potentially resectable liver metastases.

BACKGROUND AND OBJECTIVES: The optimal treatment sequence in stage IV rectal cancer (RC) with synchronous liver metastases (SLM) remains undefined. Here, we compared outcomes between patients treated with the bowel-first approach (BFA) or the liver-first approach (LFA). METHODS: Consecutive patients diagnosed with stage IV RC with SLM and who underwent complete resection were included. Both groups were matched using propensity scores. Differences in postoperative outcome, local control, and long-term survival were studied. In addition, a decision analysis (DA) model was built using TreeAge Pro to define the approach that results in the highest treatment completion rate. RESULTS: During a 12-year period, 52 patients were identified, 21 and 31 of whom underwent the BFA and the LFA, respectively. Twenty-eight patients were matched; patients treated with the BFA experienced a longer median OS (50.0 vs 33.0 months; P = .40) and higher 5-year OS (42.9% vs 28.6%). The DA defined the BFA to be superior when the failure threshold (ie, no R0 resection, treatment discontinuation regardless of cause) for colectomy is less than 28.6%. CONCLUSIONS: In stage IV rectal cancer with SLM, either the BFA or the LFA result in similar long-term outcomes. Treatment should be tailored according to clinicopathological variables.