Development, External Validation, and Visualization of Machine Learning Models for Predicting Occurrence of Acute Kidney Injury after Cardiac Surgery.

Background: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a major complication that results in short- and long-term mortality among patients. Here, we adopted machine learning algorithms to build prediction models with the overarching goal of identifying patients who are at a high risk of such unfavorable kidney outcomes. Methods: A total of 1686 patients (development cohort) and 422 patients (validation cohort), with 126 pre- and intra-operative variables, were recruited from the First Medical Centre and the Sixth Medical Centre of Chinese PLA General Hospital in Beijing, China, respectively. Analyses were performed using six machine learning techniques, namely K-nearest neighbor, logistic regression, decision tree, random forest (RF), support vector machine, and neural network, and the APPROACH score, a previously established risk score for CSA-AKI. For model tuning, optimal hyperparameter was achieved by using GridSearch with 5-fold cross-validation from the scikit-learn library. Model performance was externally assessed via the receiver operating characteristic (ROC) and decision curve analysis (DCA). Explainable machine learning was performed using the Python SHapley Additive exPlanation (SHAP) package and Seaborn library, which allow the calculation of marginal contributory SHAP value. Results: 637 patients (30.2%) developed CSA-AKI within seven days after surgery. In the external validation, the RF classifier exhibited the best performance among the six machine learning techniques, as shown by the ROC curve and DCA, while the traditional APPROACH risk score showed a relatively poor performance. Further analysis found no specific causative factor contributing to the development of CSA-AKI; rather, the development of CSA-AKI appeared to be a complex process resulting from a complex interplay of multiple risk factors. The SHAP summary plot illustrated the positive or negative contribution of RF-top 20 variables and extrapolated risk of developing CSA-AKI at individual levels. The Seaborn library showed the effect of each single feature on the model output of the RF prediction. Conclusions: Efficient machine learning approaches were successfully established to predict patients with a high probability of developing acute kidney injury after cardiac surgery. These findings are expected to help clinicians to optimize treatment strategies and minimize postoperative complications. Clinical Trial Registration: The study protocol was registered at the ClinicalTrials Registration System (https://www.clinicaltrials.gov/, #NCT04966598) on July 26, 2021.

A Mesenchymal stem cell Aging Framework, from Mechanisms to Strategies.

Mesenchymal stem cells (MSCs) are extensively researched for therapeutic applications in tissue engineering and show significant potential for clinical use. Intrinsic or extrinsic factors causing senescence may lead to reduced proliferation, aberrant differentiation, weakened immunoregulation, and increased inflammation, ultimately limiting the potential of MSCs. It is crucial to comprehend the molecular pathways and internal processes responsible for the decline in MSC function due to senescence in order to devise innovative approaches for rejuvenating senescent MSCs and enhancing MSC treatment. We investigate the main molecular processes involved in senescence, aiming to provide a thorough understanding of senescence-related issues in MSCs. Additionally, we analyze the most recent advancements in cutting-edge approaches to combat MSC senescence based on current research. We are curious whether the aging process of stem cells results in a permanent "memory" and if cellular reprogramming may potentially revert the aging epigenome to a more youthful state.

Cocktail Cell-Reprogrammed Hydrogel Microspheres Achieving Scarless Hair Follicle Regeneration.

The scar repair inevitably causes damage of skin function and loss of skin appendages such as hair follicles (HF). It is of great challenge in wound repair that how to intervene in scar formation while simultaneously remodeling HF niche and inducing in situ HF regeneration. Here, chemical reprogramming techniques are used to identify a clinically chemical cocktail (Tideglusib and Tamibarotene) that can drive fibroblasts toward dermal papilla cell (DPC) fate. Considering the advantage of biomaterials in tissue repair and their regulation in cell behavior that may contributes to cellular reprogramming, the artificial HF seeding (AHFS) hydrogel microspheres, inspired by the natural processes of "seeding and harvest", are constructed via using a combination of liposome nanoparticle drug delivery system, photoresponsive hydrogel shell, positively charged polyamide modification, microfluidic and photocrosslinking techniques. The identified chemical cocktail is as the core nucleus of AHFS. In vitro and in vivo studies show that AHFS can regulate fibroblast fate, induce fibroblast-to-DPC reprogramming by activating the PI3K/AKT pathway, finally promoting wound healing and in situ HF regeneration while inhibiting scar formation in a two-pronged translational approach. In conclusion, AHFS provides a new and effective strategy for functional repair of skin wounds.

A versatile attention-based neural network for chemical perturbation analysis and its potential to aid surgical treatment: A experimental study.

Deep learning models have emerged as rapid, accurate, and effective approaches for clinical decisions. Through a combination of drug screening and deep learning models, drugs that may benefit patients before and after surgery can be discovered to reduce the risk of complications or speed recovery. However, most existing drug prediction methods have high data requirements and lack interpretability, which has a limited role in adjuvant surgical treatment. To address these limitations, we propose the attention-based convolution transpositional interfusion network (ACTIN) for flexible and efficient drug discovery. ACTIN leverages the graph convolution and the transformer mechanism, utilizing drug and transcriptome data to assess the impact of chemical pharmacophores containing certain elements on gene expression. Remarkably, just with only 393 training instances, only one-tenth of the other models, ACTIN achieves state-of-the-art performance, demonstrating its effectiveness even with limited data. By incorporating chemical element embedding disparity and attention mechanism-based parameter analysis, it identifies the possible pharmacophore containing certain elements that could interfere with specific cell lines, which is particularly valuable for screening useful pharmacophores for new drugs tailored to adjuvant surgical treatment. To validate its reliability, we conducted comprehensive examinations by utilizing transcriptome data from the lung tissue of fatal COVID-19 patients as additional input for ACTIN, we generated novel lead chemicals that align with clinical evidence. In summary, ACTIN offers insights into the perturbation biases of elements within pharmacophore on gene expression, which holds the potential for guiding the development of new drugs that benefit surgical treatment.

Biomaterial-based mechanical regulation facilitates scarless wound healing with functional skin appendage regeneration.

Scar formation resulting from burns or severe trauma can significantly compromise the structural integrity of skin and lead to permanent loss of skin appendages, ultimately impairing its normal physiological function. Accumulating evidence underscores the potential of targeted modulation of mechanical cues to enhance skin regeneration, promoting scarless repair by influencing the extracellular microenvironment and driving the phenotypic transitions. The field of skin repair and skin appendage regeneration has witnessed remarkable advancements in the utilization of biomaterials with distinct physical properties. However, a comprehensive understanding of the underlying mechanisms remains somewhat elusive, limiting the broader application of these innovations. In this review, we present two promising biomaterial-based mechanical approaches aimed at bolstering the regenerative capacity of compromised skin. The first approach involves leveraging biomaterials with specific biophysical properties to create an optimal scarless environment that supports cellular activities essential for regeneration. The second approach centers on harnessing mechanical forces exerted by biomaterials to enhance cellular plasticity, facilitating efficient cellular reprogramming and, consequently, promoting the regeneration of skin appendages. In summary, the manipulation of mechanical cues using biomaterial-based strategies holds significant promise as a supplementary approach for achieving scarless wound healing, coupled with the restoration of multiple skin appendage functions.

HucMSC-Exo Induced N2 Polarization of Neutrophils: Implications for Angiogenesis and Tissue Restoration in Wound Healing.

Background: Neutrophils rapidly accumulate in large numbers at sites of tissue damage, exhibiting not only their well-known bactericidal capabilities but also playing crucial roles in angiogenesis and tissue repair. While exosomes derived from human umbilical cord mesenchymal stem cells (HucMSC-Exo) have emerged as a promising therapeutic tool, their exact mechanisms of action remain partly elusive. We hypothesize that HucMSC-Exo treatment may modulate neutrophil phenotypes, thereby significantly influencing wound healing outcomes. Methods: HucMSC-Exo were isolated via ultracentrifugation and subsequently administered through subcutaneous injection into full-thickness cutaneous wounds in mice. To determine the impact of host neutrophils on the healing effects of HucMSC-Exo in skin injuries, strategies including neutrophil depletion and adoptive transfer were employed. Flow cytometry was used to evaluate the proportion of N2 subtype neutrophils in both normal and diabetic wounds, and the effect of HucMSC-Exo on this proportion was assessed. Furthermore, the mitochondrial metabolic reprogramming driven by HucMSC-Exo during N2 polarization was investigated through JC1 staining, ATP quantification, fatty acid uptake assays, and assessment of FAO-related genes (Cpt1b, Acadm, and Acadl). Results: Depleting host neutrophils strikingly dampened prohealing effect of HucMSC-Exo on skin injury, while adoptive transfer of bone marrow neutrophils rescued this process. During normal healing process, some neutrophils expressed N2 markers, in contrast, diabetic wounds exhibited a reduced expression of N2 markers. After treatment with HucMSC-Exo, most neutrophils increased the phosphorylation of STAT6, leading to mitochondrial metabolic reprogramming and thus acquired an N2 phenotype. These N2 neutrophils, polarized by HucMSC-Exo, boosted the release of proangiogenic factors, particularly BV8, a myeloid cell-derived proangiogenic factor, and induced angiogenesis thereby favoring tissue restoration. Conclusion: This research uniquely demonstrates the identification of N2 neutrophils in skin injury and shows that HucMSC-Exo could skew neutrophils toward N2 phenotype, enhancing our insight into how cells react to HucMSC-Exo.

Sebaceous gland organoid engineering.

Sebaceous glands (SGs), as holocrine-secreting appendages, lubricate the skin and play a central role in the skin barrier. Large full-thickness skin defects cause overall architecture disruption and SG loss. However, an effective strategy for SG regeneration is lacking. Organoids are 3D multicellular structures that replicate key anatomical and functional characteristics of in vivo tissues and exhibit great potential in regenerative medicine. Recently, considerable progress has been made in developing reliable procedures for SG organoids and existing SG organoids recapitulate the main morphological, structural and functional features of their in vivo counterparts. Engineering approaches empower researchers to manipulate cell behaviors, the surrounding environment and cell-environment crosstalk within the culture system as needed. These techniques can be applied to the SG organoid culture system to generate functionally more competent SG organoids. This review aims to provide an overview of recent advancements in SG organoid engineering. It highlights some potential strategies for SG organoid functionalization that are promising to forge a platform for engineering vascularized, innervated, immune-interactive and lipogenic SG organoids. We anticipate that this review will not only contribute to improving our understanding of SG biology and regeneration but also facilitate the transition of the SG organoid from laboratory research to a feasible clinical application.

Customized Proteinaceous Nanoformulation for In Vivo Chemical Reprogramming.

Sweat gland (SwG) regeneration is crucial for the functional rehabilitation of burn patients. In vivo chemical reprogramming that harnessing the patient's own cells in damaged tissue is of substantial interest to regenerate organs endogenously by pharmacological manipulation, which could compensate for tissue loss in devastating diseases and injuries, for example, burns. However, achieving in vivo chemical reprogramming is challenging due to the low reprogramming efficiency and an unfavorable tissue environment. Herein, this work has developed a functionalized proteinaceous nanoformulation delivery system containing prefabricated epidermal growth factor structure for on-demand delivery of a cocktail of seven SwG reprogramming components to the dermal site. Such a chemical reprogramming system can efficiently induce the conversion of epidermal keratinocytes into SwG myoepithelial cells, resulting in successful in situ regeneration of functional SwGs. Notably, in vivo chemical reprogramming of SwGs is achieved for the first time with an impressive efficiency of 30.6%, surpassing previously reported efficiencies. Overall, this proteinaceous nanoformulation provides a platform for coordinating the target delivery of multiple pharmacological agents and facilitating in vivo SwG reprogramming by chemicals. This advancement greatly improves the clinical accessibility of in vivo reprogramming and offers a non-surgical, non-viral, and cell-free strategy for in situ SwG regeneration.