Pt/NiFe-LDH hybrids for quantification and qualification of polyphenols.

Polyphenols with antioxidant properties are of significant interest in medical and pharmaceutical applications. Given the diverse range of activities of polyphenols in vivo, accurate detection of these compounds plays a crucial role in nutritional surveillance and pharmaceutical development. Yet, the efficient quantitation of polyphenol contents and qualification of monomer compositions present a notable challenge when studying polyphenol bioavailability. In this study, platinum-modified nickel-iron layered double hydroxide (Pt/NiFe-LDH hybrids) were designed to mimic peroxidases for colorimetric analysis and act as enhanced matrices for laser desorption/ionization mass spectrometry (LDI MS) to quantify and qualify polyphenols. The hybrids exhibited an enzymatic activity of 33.472 U/mg for colorimetric assays, facilitating the rapid and direct quantitation of total tea polyphenols within approximately 1 min. Additionally, the heterogeneous structure and exposed hydroxyl groups on the hybrid surface contributed to photoelectric enhancement and in-situ enrichment of polyphenols in LDI MS. This study introduces an innovative approach to detect polyphenols using advanced materials, potentially inspiring the future development and applications of other photoactive nanomaterials.

Small extracellular vesicles: Non-negligible vesicles in tumor progression, diagnosis, and therapy.

Small extracellular vesicles (sEVs) such as exosomes are nanoscale membranous particles (<200 nm) that have emerged as crucial targets for liquid biopsy and as promising drug delivery vehicles. They play a significant role in tumor progression as intercellular messengers. They can serve as biomarkers for tumor diagnosis and as drug carriers for cancer treatment. This article reviews recent studies on sEVs in oncology and explores their potential as biomarkers and drug delivery vehicles. Following tumorigenesis, sEVs in the tumor microenvironment (TME) and circulatory system undergo modifications to regulate various events in the TME, including angiogenesis, epithelial-mesenchymal transition (EMT), and tumor immunity, with either pro- or anti-tumor effects. sEVs have been investigated for use as diagnostic and prognostic biomarkers for a variety of tumors, including lung cancer, melanoma, breast cancer, prostate cancer, and hepatocellular carcinoma. sEVs can be used for cancer therapy by packaging drugs or proteins into them through pre- and post-isolation modification techniques. The clinical trials of sEVs as biomarkers and drug carriers are also summarized. Finally, the challenges in the use of sEVs are described and the possible approaches to tackling them are suggested. Overall, sEVs will advance the precision cancer medicine and has shown great potential in clinical applications.

Hypoxia-induced circ-CDYL-EEF1A2 transcriptional complex drives lung metastasis of cancer stem cells from hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is often associated with poor outcomes due to lung metastasis. ICAM-1+ circulating tumor cells, termed circulating cancer stem cells (CCSCs), possess stem cell-like characteristics. However, it is still unexplored how their presence indicates lung metastasis tendency, and particularly, what mechanism drives their lung metastasis. Here, we demonstrated that a preoperative CCSC count in 5 mL of blood (CCSC5) of >3 was a risk factor for lung metastasis in clinical HCC patients. The CSCs overexpressed with circ-CDYL entered the bloodstream and developed lung metastases in mice. Mechanistically, circ-CDYL promoted COL14A1 expression and thus ERK signaling to facilitate epithelial-mesenchymal transition. Furthermore, we uncovered that an RNA-binding protein, EEF1A2, acted as a novel transcriptional (co-) factor to cooperate with circ-CDYL and initiate COL14A1 transcription. A high circ-CDYL level is caused by HIF-1⍺-mediated transcriptional upregulation of its parental gene CDYL and splicing factor EIF4A3 under a hypoxia microenvironment. Hence, the hypoxia microenvironment enables the high-tendency lung metastasis of ICAM-1+ CCSCs through the HIF-1⍺/circ-CDYL-EEF1A2/COL14A1 axis, potentially allowing clinicians to preoperatively detect ICAM-1+ CCSCs as a real-time biomarker for precisely deciding HCC treatment strategies.

Non-coding RNAs: a promising target for early metastasis intervention.

ABSTRACT: Metastases account for the overwhelming majority of cancer-associated deaths. The dissemination of cancer cells from the primary tumor to distant organs involves a complex process known as the invasion-metastasis cascade. The underlying biological mechanisms of metastasis, however, remain largely elusive. Recently, the discovery and characterization of non-coding RNAs (ncRNAs) have revealed the diversity of their regulatory roles, especially as key contributors throughout the metastatic cascade. Here, we review recent progress in how three major types of ncRNAs (microRNAs, long non-coding RNAs, and circular RNAs) are involved in the multistep procedure of metastasis. We further examine interactions among the three ncRNAs as well as current progress in their regulatory mechanisms. We also propose the prevention of metastasis in the early stages of cancer progression and discuss current translational studies using ncRNAs as targets for metastasis diagnosis and treatments. These studies provide insights into developing more effective strategies to target metastatic relapse.

Single-cell RNA sequencing of peripheral blood reveals immune cell dysfunction in premature ovarian insufficiency.

Background: Premature ovarian insufficiency (POI) is one of the most common causes of female infertility and the etiology is highly heterogeneous. Most cases are idiopathic and the pathogenesis remains unclear. Previous studies proved that the immune system plays a crucial role in POI. However, the precise role of immune system remains unclear. This study aimed to analyze the characteristics of peripheral blood mononuclear cells (PBMC) from patients with POI by single-cell RNA sequencing (scRNA-seq) and to explore the potential involvement of immune response in idiopathic POI. Methods: PBMC was collected from three normal subjects and three patients with POI. PBMC was subjected to scRNA-seq to identify cell clusters and differently expressed genes (DEGs). Enrichment analysis and cell-cell communication analysis were performed to explore the most active biological function in the immune cells of patients with POI. Results: In total, 22 cell clusters and 10 cell types were identified in the two groups. Compared with normal subjects, the percentage of classical monocytes and NK cells was decreased, the abundance of plasma B cells was increased, and CD4/CD8 ratio was significantly higher in POI. Furthermore, upregulation of IGKC, IFITM1, CD69, JUND and downregulation of LYZ, GNLY, VCAN, and S100A9 were identified, which were enriched in NK cell-mediated cytotoxicity, antigen processing and presentation, and IL-17 signaling pathway. Among them, IGHM and LYZ were respectively the most significantly upregulated and downregulated genes among all cell clusters of POI. The strength of cell-cell communication differed between the healthy subjects and patients with POI, and multiple signaling pathways were assessed. The TNF pathway was found to be unique in POI with classical monocytes being the major target and source of TNF signaling. Conclusions: Dysfunction of cellular immunity is related to idiopathic POI. Monocytes, NK cells, and B cells, and their enriched differential genes may play a role in the development of idiopathic POI. These findings provide novel mechanistic insight for understanding the pathogenesis of POI.

Alterations of commensal microbiota are associated with pancreatic cancer.

BACKGROUND: Dysbiosis commonly occurs in pancreatic cancer, but its specific characteristics and interactions with pancreatic cancer remain obscure. MATERIALS AND METHODS: The 16S rRNA sequencing method was used to analyze multisite (oral and gut) microbiota characteristics of pancreatic cancer, chronic pancreatitis, and healthy controls. Differential analysis was used to identify the pancreatic cancer-associated genera and pathways. A random forest algorithm was adopted to establish the diagnostic models for pancreatic cancer. RESULTS: The chronic pancreatitis group exhibited the lowest microbial diversity, while no significant difference was found between the pancreatic cancer group and healthy controls group. Diagnostic models based on the characteristics of the oral (area under the curve (AUC) 0.916, 95% confidence interval (CI) 0.832-1) or gut (AUC 0.856; 95% CI 0.74, 0.972) microbiota effectively discriminate the pancreatic cancer samples in this study, suggesting saliva as a superior sample type in terms of detection efficiency and clinical compliance. Oral pathogenic genera (Granulicatella, Peptostreptococcus, Alloprevotella, Veillonella, etc.) and gut opportunistic genera (Prevotella, Bifidobacterium, Escherichia/Shigella, Peptostreptococcus, Actinomyces, etc.), were significantly enriched in pancreatic cancer. The 16S function prediction analysis revealed that inflammation, immune suppression, and barrier damage pathways were involved in the course of pancreatic cancer. CONCLUSION: This study comprehensively described the microbiota characteristics of pancreatic cancer and suggested potential microbial markers as non-invasive tools for pancreatic cancer diagnosis.

Chronological changes of viral shedding in adult inpatients with Omicron infection in Shanghai, China.

Background: Coronavirus disease 2019 (COVID-19) caused by the Omicron variant occurred in Shanghai, China, but its clinical characteristics and virology have not been comprehensively described. Methods: This retrospective cohort study included adult inpatients (≥18 years) diagnosed with COVID-19 at Changhai Hospital. Laboratory and clinical data were obtained from electronic medical records to investigate the clinical characteristics of COVID-19 and the variations in the patients' laboratory indexes were examined. Results: The symptoms of COVID-19 caused by the Omicron variant were relatively mild. Upper respiratory tract specimens yielded higher positive detection rates than lower respiratory tract and intestinal specimens. Peak COVID-19 viral load was reached at the time of admission; quantification cycle (Cq) values increased to approximately 35 after 8.54 days. In vivo viral shedding duration correlated with age and disease severity (p<0.05). The older the patient and the more severe the disease, the longer the duration of viral shedding was. Portion parameters of blood routine, coagulative function, clinical chemistry, and inflammatory factor showed a certain correlation with the SARS-CoV-2 viral load. Conclusions: Virus replication and shedding are rapid in Omicron-positive patients; COVID-19 in these patients is characterized by acute onset, mild symptoms, and fast recovery. Older patients and those with more severe disease demonstrate prolonged virus shedding. Routine hematological indexes can reveal disease severity and help clinically evaluate the patient's condition.

Dual-modal nanoplatform integrated with smartphone for hierarchical diabetic detection.

On-site screening of diabetes and precise diagnosis of diabetic complications may provide a conduit for early intervention and disease burden reduction. However, stratified metabolic analysis needs designed materials for colorimetric detection of targeted biomarkers and direct metabolic fingerprinting of the native blood. Here, an advanced dual-modal nanoplatform is constructed based on PdPtAu alloys, which serve both as the nanoenzymes in colorimetric sensing for targeted metabolite quantitation and as matrix in laser desorption/ionization mass spectrometry for untargeted metabolic fingerprinting. The platform achieved rapid glucose quantitation toward point-of-care testing of 27 participants and identified diabetic retinopathy from diabetic population with a sensitivity and specificity of 84.6%. We further assessed the generalizability of the nanoplatform for real-case applications, through the captured digital images and computing resources equipped in smartphones. The results advance the design of material-based platforms for stratified metabolic analysis and display promise to fit in the current hierarchical medical system in practice.

Integrated analysis revealing the role of TET3-mediated MUC13 promoter hypomethylation in hepatocellular carcinogenesis.

Aim: To explore the function and underlying mechanism of MUC13 in hepatocellular carcinoma (HCC) oncogenesis. Materials & Methods: Online databases and software were used to perform analyses of expression, methylation and enrichment pathway. Experiments were performed to confirm the results using HCC cells in vitro. Results: MUC13 was upregulated in HCC and liver cancer stem cells (CSCs) and had a positive influence on CSC generation. Further analyses revealed that MUC13 with promoter hypomethylated was regulated by DNA demethylase TET3, which was overexpressed in HCC and liver CSCs. Conclusion: These results strongly suggested that high TET3 expression in liver CSCs may mediate MUC13 upregulation via promoter hypomethylation and thereby contribute to hepatocellular carcinogenesis.

To understand the function and mechanism of MUC13 in hepatocellular carcinogenesis, online databases and software were used to analyze MUC13 expression, promoter methylation and enrichment pathway. Experiments were also performed to further confirm the results in vitro. MUC13 was upregulated in hepatocellular carcinoma (HCC) and had a positive influence on cancer stem cell (CSC) generation. Further analyses revealed that MUC13 with promoter hypomethylated was regulated by DNA demethylase TET3, which was overexpressed in HCC and liver CSCs. Importantly, it was revealed that MUC13 with promoter hypomethylated, was regulated by TET3, which was overexpressed in HCC and liver CSCs. These results strongly suggest that high TET3 expression in liver CSCs may mediate promoter hypomethylation and expression upregulation of MUC13, thereby contributing to hepatocellular carcinogenesis.

Integrated analysis identifies S100A16 as a potential prognostic marker for pancreatic cancer.

BACKGROUND: The new S100 protein family member S100A16 is functionally expressed in various cancers. This study explored the prognostic value and potential role of S100A16 in pancreatic cancer (PC). METHODS: RNA-seq and clinical data were obtained from The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA-PAAD) dataset to compare the expression level of S100A16 between groups. The genes co-expressed with S100A16 in TCGA-PAAD were analyzed using cBioPortal. Gene Ontology and Kyoto Encyclopedia of Genes and genomes enrichment analyses were also performed on these genes. Pathways related to S100A16 expression dysregulation were explored using gene set enrichment analysis. The Tumor Immune Estimation Resource was used to analyze the correlation between S100A16 and infiltrating immune cells. The Kaplan-Meier method and Cox analyses were used to assess the prognostic significance of S100A16 for PC. RESULTS: The S100A16 expression level was high in PC and increased with the degree of malignancy. The S100A16 functions in PC were mainly enriched in the immune modules, but negatively correlated with the immune activity (T-cell, cytokine, immune, co-receptor, signaling adaptor, cell adhesion molecule, chemokine, and JAK/STAT signaling) and infiltration level (T cells and macrophages). The strongest negative correlation was observed between the expression of CD8+ T cells and S100A16. Furthermore, high S100A16 expression also indicated worse overall survival and, therefore, worse prognosis of PC. CONCLUSION: S100A16 is a potential independent prognostic marker and immunotherapy target for PC. Mechanistically, S100A16 potentially affects prognosis by extensive immunosuppression, including the inhibition of the anti-tumor immune response of CD8+ T cells.

SNORA23 inhibits HCC tumorigenesis by impairing the 2'-O-ribose methylation level of 28S rRNA.

OBJECTIVE: The dysregulation of ribosome biogenesis is associated with the progression of numerous tumors, including hepatocellular carcinoma (HCC). Small nucleolar RNAs (snoRNAs) regulate ribosome biogenesis by guiding the modification of ribosomal RNAs (rRNAs). However, the underlying mechanism of this process in HCC remains elusive. METHODS: RNA immunoprecipitation and sequencing were used to analyze RNAs targeted by ribosome proteins. The biological functions of SNORA23 were examined in HCC cells and a xenograft mouse model. To elucidate the underlying mechanisms, the 2'-O-ribose methylation level of rRNAs was evaluated by qPCR, and the key proteins in the PI3K/Akt/mTOR pathway were detected using Western blot. RESULTS: Twelve snoRNAs were found to co-exist in 4 cancer cell lines using RPS6 pull-down assays. SNORA23 was downregulated in HCC and correlated with the poor prognoses of HCC patients. SNORA23 inhibited the proliferation, migration, and invasion of HCC cells both in vitro and in vivo. We also found that SNORA23 regulated ribosome biogenesis by impairing 2'-O-ribose methylation of cytidine4506 of 28S rRNA. Furthermore, SNORA23, which is regulated by the PI3K/Akt/mTOR signaling pathway, significantly inhibited the phosphorylation of 4E binding protein 1. SNORA23 and rapamycin blocked the PI3K/AKT/mTOR signaling pathway and impaired HCC growth in vivo. CONCLUSIONS: SNORA23 exhibited antitumor effects in HCC and together with rapamycin, provided a promising therapeutic strategy for HCC treatment.

Erratum: Circ-MALAT1 Functions as Both an mRNA Translation Brake and a microRNA Sponge to Promote Self-Renewal of Hepatocellular Cancer Stem Cells.

[This corrects the article DOI: 10.1002/advs.201900949.].

Peptide SMIM30 promotes HCC development by inducing SRC/YES1 membrane anchoring and MAPK pathway activation.

BACKGROUND & AIMS: Growing evidence shows that some non-coding RNAs (ncRNAs) contain small open reading frames (smORFs) that are translated into short peptides. Herein, we aimed to determine where and how these short peptides might promote hepatocellular carcinoma (HCC) development. METHODS: We performed an RNA-immunoprecipitation followed by high-throughput sequencing (RIP-seq) assay with an antibody against ribosomal protein S6 (RPS6) on 4 cancer cell lines. Focusing on 1 long non-coding RNA (lncRNA), LINC00998, we used qPCR and public databases to evaluate its expression level in patients with HCC. Special vectors were constructed to confirm its coding potential. We also explored the function and mechanism of LINC00998-encoded peptide in tumor growth and metastasis. RESULTS: We discovered that many lncRNAs bind to RPS6 in cancer cells. One of these lncRNAs, LINC00998, encoded a small endogenous peptide, termed SMIM30. SMIM30, rather than the RNA itself, promoted HCC tumorigenesis by modulating cell proliferation and migration, and its level was correlated with poor survival in patients with HCC. Furthermore, SMIM30 was transcribed by c-Myc and then drove the membrane anchoring of the non-receptor tyrosine kinases SRC/YES1. Moreover, the downstream MAPK signaling pathway was activated by SRC/YES1. CONCLUSIONS: Our results not only unravel a new mechanism of HCC tumorigenesis promoted by ncRNA-encoded peptides, but also suggest that these peptides can serve as a new target for HCC cancer therapy and a new biomarker for HCC diagnosis and prognosis. LAY SUMMARY: Very little is known about how peptides activate signaling pathways that play a crucial role in diseases such as cancer. Specifically, we reported on a conserved peptide encoded by LINC00998, SMIM30. This peptide promoted the tumorigenesis of hepatocellular carcinoma (HCC) by modulating cell proliferation and migration. Of note, it bound the non-receptor tyrosine kinases, SRC/YES1, to drive their membrane anchoring and phosphorylation, activating the downstream MAPK signaling pathway. Our work not only unravels a new mechanism of HCC tumorigenesis promoted by peptides, but also demonstrates how the peptide works to activate a signaling pathway.

Methylation Status of the Nanog Promoter Determines the Switch between Cancer Cells and Cancer Stem Cells.

Cancer stem cells (CSCs) are the main cause of tumor development, metastasis, and relapse. CSCs are thus considered promising targets for cancer therapy. However, it is hard to eradicate CSCs due to their inherent plasticity and heterogeneity, and the underlying mechanism of the switch between non-CSCs and CSCs remains unclear. Here, it is shown that miR-135a combined with SMYD4 activates Nanog expression and induces the switch of non-CSCs into CSCs. The miR-135a level, once elevated, lowers the methylation level of the CG5 site in the Nanog promoter by directly targeting DNMT1. SMYD4 binds to the unmethylated Nanog promoter to activate Nanog expression in Nanog-negative tumor cells. The in vivo regulation of miR-135a levels could significantly affect both the CSCs proportion and tumor progression. These findings indicate that DNA methylation of the Nanog promoter modulates the switch of non-CSCs into CSCs under the control of the miRNA-135 level. In addition, the related pathways, miR-135a/DNMT1 and SMYD4, involved in these processes are potential targets for CSC-targeted therapy.

Circ-MALAT1 Functions as Both an mRNA Translation Brake and a microRNA Sponge to Promote Self-Renewal of Hepatocellular Cancer Stem Cells.

Both circular RNAs (circRNAs) and cancer stem cells (CSCs) are separately known to be involved in cancer, but their interaction remains unclear. Here, the regulation of hepatocellular CSC self-renewal is discovered by a circRNA, circ-MALAT1, which is produced by back-splicing of a long noncoding RNA, MALAT1. Circ-MALAT1 is highly expressed in CSCs from clinical hepatocellular carcinoma samples under the mediation of an RNA-binding protein, AUF1. Surprisingly, circMALAT1 functions as a brake in ribosomes to retard PAX5 mRNA translation and promote CSCs' self-renewal by forming an unprecedented ternary complex with both ribosomes and mRNA. The discovered braking mechanism of a circRNA, termed mRNA braking, along with its more traditional role of miRNA sponging, uncovers a dual-faceted pattern of circRNA-mediated post-transcriptional regulation for maintaining a specific cell state.

A panel of five plasma proteins for the early diagnosis of hepatitis B virus-related hepatocellular carcinoma in individuals at risk.

BACKGROUND: To improve the early diagnosis of hepatocellular carcinoma (HCC), more effective diagnostic biomarkers are needed. A combination of biomarkers is reported to distinguish individuals with early-stage HCC from at-risk individuals. METHODS: Participants in this study were recruited from six hospitals in China. Literature review was used to choose 19 candidate proteins, a case-control study in the discovery stage was used to identify five proteins (P5) that constituted a diagnostic model. In the training and validation stages, the effectiveness of P5 for detecting early-stage HCC was tested (cross-sectional study). Finally, a nested case-control study independent of the other stages was set up to evaluate the P5 in the preclinical diagnosis of HCC. FINDINGS: Between February 2013 and June 2017, a total of 1396 participants were recruited. A panel of 5 proteins (P5: OPN, GDF15, NSE, TRAP5 and OPG) showed high diagnostic accuracy when differentiating the early-stage HCC from the at-risk group, with AUCs of 0·892, 0·907 and 0·852 for the training stage, validation cohort 1 and cohort 2 data sets, respectively. In the prediction set, the sensitivity of P5 for diagnosing preclinical HCC increased with time, starting from 12 months before to the time of definitive clinical diagnosis (range, 46·15% to 86·67%). INTERPRETATION: The P5 panel has the potential to screen populations at high risk of developing HCC and can enable the early diagnosis of HCC. FUNDING: Research supported by grants from eight funds. All sources of funding were declared at the end of the text.

Peptides encoded by noncoding genes: challenges and perspectives.

In recent years, noncoding gene (NCG) translation events have been frequently discovered. The resultant peptides, as novel findings in the life sciences, perform unexpected functions of increasingly recognized importance in many fundamental biological and pathological processes. The emergence of these novel peptides, in turn, has advanced the field of genomics while indispensably aiding living organisms. The peptides from NCGs serve as important links between extracellular stimuli and intracellular adjustment mechanisms. These peptides are also important entry points for further exploration of the mysteries of life that may trigger a new round of revolutionary biotechnological discoveries. Insights into NCG-derived peptides will assist in understanding the secrets of life and the causes of diseases, and will also open up new paths to the treatment of diseases such as cancer. Here, a critical review is presented on the action modes and biological functions of the peptides encoded by NCGs. The challenges and future trends in searching for and studying NCG peptides are also critically discussed.

Nosocomial spread of OXA-232-producing Klebsiella pneumoniae ST15 in a teaching hospital, Shanghai, China.

BACKGROUND: The spread and outbreak of Enterobacteriaceae producing OXA-48-like carbapenemases have become more and more prevalent in China. RESULTS: A total of 62 non-duplicated OXA-232-producing K. pneumoniae (OXA232Kp) were isolated between 2015 and 2017. An outbreak of OXA232Kp was observed in burn ICU. The 62 OXA232Kp isolates were all belongs to ST15 and categorized into two PFGE types (A and B). Type A was dominated of the isolates, which contained 61 clinical isolates and divided into 10 subtypes (A1-A10). In addition, most of OXA232Kp strains exhibited low-level carbapenems resistance. All strains carried a 6141 bp ColKP3 plasmid harboring the blaOXA-232 gene which is highly homologous to other blaOXA-232-bearing plasmids involved in other studies in eastern China. CONCLUSIONS: In this study, clone transmission of OXA232Kp ST15was observed. Highly significant homology among the blaOXA-232-bearing plasmids indicated the important role of the 6.1 kb ColE-like plasmid on the prevalence of blaOXA-232 gene in China.

Spontaneous evolution of human skin fibroblasts into wound-healing keratinocyte-like cells.

Producing keratinocyte cells (KCs) in large scale is difficult due to their slow proliferation, disabling their use as seed cells for skin regeneration and wound healing. Cell reprogramming is a promising inducer-based approach to KC production but only reaches very low cellular conversion. Here we reported a unique cellular conversion phenomenon, where human skin fibroblasts (FBs) were spontaneously converted into keratinocyte-like cells (KLCs) over the time without using any inducers. Methods: FBs were routinely cultured for more than 120 days in regular culture medium. Characteristics of KLCs were checked at the molecular and cellular level. Then the functionality and safety of the KLCs were verified by wound healing and tumorigenicity assay, respectively. To identify the mechanism of the cell conversion phenomenon, high-throughput RNA sequencing was also performed. Results: The global conversion started on day 90 and reached 90% on day 110. The KLCs were as functional and effective as KCs in wound healing without causing oncogenicity. The conversion was regulated via a PI3K-AKT signaling pathway mediated by a long non-coding RNA, LINC00672. Modulating the pathway could shorten the conversion time to 14 days. Conclusion: The discovered FBs-KLCs conversion in the study might open a new avenue to the scalable production of cell sources needed for regenerating skins and healing large-area wounds.