npj Regenerative Medicine最新文献

{"title":"Topically-applied collagen-binding serum albumin-fused interleukin-4 modulates wound microenvironment in non-healing wounds.","authors":"Abigail L Lauterbach, Rachel P Wallace, Aaron T Alpar, Kirsten C Refvik, Joseph W Reda, Ako Ishihara, Taryn N Beckman, Anna J Slezak, Yukari Mizukami, Aslan Mansurov, Suzana Gomes, Jun Ishihara, Jeffrey A Hubbell","doi":"10.1038/s41536-023-00326-y","DOIUrl":"10.1038/s41536-023-00326-y","url":null,"abstract":"<p><p>Non-healing wounds have a negative impact on quality of life and account for many cases of amputation and even early death among patients. Diabetic patients are the predominate population affected by these non-healing wounds. Despite the significant clinical demand, treatment with biologics has not broadly impacted clinical care. Interleukin-4 (IL-4) is a potent modulator of the immune system, capable of skewing macrophages towards a pro-regeneration phenotype (M2) and promoting angiogenesis, but can be toxic after frequent administration and is limited by its short half-life and low bioavailability. Here, we demonstrate the design and characterization of an engineered recombinant interleukin-4 construct. We utilize this collagen-binding, serum albumin-fused IL-4 variant (CBD-SA-IL-4) delivered in a hyaluronic acid (HA)-based gel for localized application of IL-4 to dermal wounds in a type 2 diabetic mouse model known for poor healing as proof-of-concept for improved tissue repair. Our studies indicate that CBD-SA-IL-4 is retained within the wound and can modulate the wound microenvironment through induction of M2 macrophages and angiogenesis. CBD-SA-IL-4 treatment significantly accelerated wound healing compared to native IL-4 and HA vehicle treatment without inducing systemic side effects. This CBD-SA-IL-4 construct can address the underlying immune dysfunction present in the non-healing wound, leading to more effective tissue healing in the clinic.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"49"},"PeriodicalIF":7.2,"publicationDate":"2023-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10495343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10605744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Opposing roles for TGFβ- and BMP-signaling during nascent alveolar differentiation in the developing human lung.","authors":"Tristan Frum, Peggy P Hsu, Renee F C Hein, Ansley S Conchola, Charles J Zhang, Olivia R Utter, Abhinav Anand, Yi Zhang, Sydney G Clark, Ian Glass, Jonathan Z Sexton, Jason R Spence","doi":"10.1038/s41536-023-00325-z","DOIUrl":"10.1038/s41536-023-00325-z","url":null,"abstract":"<p><p>Alveolar type 2 (AT2) cells function as stem cells in the adult lung and aid in repair after injury. The current study aimed to understand the signaling events that control differentiation of this therapeutically relevant cell type during human development. Using lung explant and organoid models, we identified opposing effects of TGFβ- and BMP-signaling, where inhibition of TGFβ- and activation of BMP-signaling in the context of high WNT- and FGF-signaling efficiently differentiated early lung progenitors into AT2-like cells in vitro. AT2-like cells differentiated in this manner exhibit surfactant processing and secretion capabilities, and long-term commitment to a mature AT2 phenotype when expanded in media optimized for primary AT2 culture. Comparing AT2-like cells differentiated with TGFβ-inhibition and BMP-activation to alternative differentiation approaches revealed improved specificity to the AT2 lineage and reduced off-target cell types. These findings reveal opposing roles for TGFβ- and BMP-signaling in AT2 differentiation and provide a new strategy to generate a therapeutically relevant cell type in vitro.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"48"},"PeriodicalIF":7.2,"publicationDate":"2023-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10492838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10596316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Publisher Correction: A postnatal network of co-hepato/pancreatic stem/progenitors in the biliary trees of pigs and humans.","authors":"Wencheng Zhang,&nbsp;Xicheng Wang,&nbsp;Giacomo Lanzoni,&nbsp;Eliane Wauthier,&nbsp;Sean Simpson,&nbsp;Jennifer Ashley Ezzell,&nbsp;Amanda Allen,&nbsp;Carolyn Suitt,&nbsp;Jonah Krolik,&nbsp;Alexander Jhirad,&nbsp;Juan Dominguez-Bendala,&nbsp;Vincenzo Cardinale,&nbsp;Domenico Alvaro,&nbsp;Diletta Overi,&nbsp;Eugenio Gaudio,&nbsp;Praveen Sethupathy,&nbsp;Guido Carpino,&nbsp;Christopher Adin,&nbsp;Jorge A Piedrahita,&nbsp;Kyle Mathews,&nbsp;Zhiying He,&nbsp;Lola McAdams Reid","doi":"10.1038/s41536-023-00323-1","DOIUrl":"10.1038/s41536-023-00323-1","url":null,"abstract":"","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"47"},"PeriodicalIF":7.2,"publicationDate":"2023-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10482821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10177194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combination human umbilical cord perivascular and endothelial colony forming cell therapy for ischemic cardiac injury.","authors":"Farwah Iqbal, Alexander Johnston, Brandon Wyse, Razieh Rabani, Poonam Mander, Banafshe Hoseini, Jun Wu, Ren-Ke Li, Andrée Gauthier-Fisher, Peter Szaraz, Clifford Librach","doi":"10.1038/s41536-023-00321-3","DOIUrl":"10.1038/s41536-023-00321-3","url":null,"abstract":"<p><p>Cell-based therapeutics are promising interventions to repair ischemic cardiac tissue. However, no single cell type has yet been found to be both specialized and versatile enough to heal the heart. The synergistic effects of two regenerative cell types including endothelial colony forming cells (ECFC) and first-trimester human umbilical cord perivascular cells (FTM HUCPVC) with endothelial cell and pericyte properties respectively, on angiogenic and regenerative properties were tested in a rat model of myocardial infarction (MI), in vitro tube formation and Matrigel plug assay. The combination of FTM HUCPVCs and ECFCs synergistically reduced fibrosis and cardiomyocyte apoptosis, while promoting favorable cardiac remodeling and contractility. These effects were in part mediated by ANGPT2, PDGF-β, and VEGF-C. PDGF-β signaling-dependent synergistic effects on angiogenesis were also observed in vitro and in vivo. FTM HUCPVCs and ECFCs represent a cell combination therapy for promoting and sustaining vascularization following ischemic cardiac injury.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"45"},"PeriodicalIF":7.2,"publicationDate":"2023-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10457300/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10096139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferric citrate and apo-transferrin enable erythroblast maturation with β-globin from hemogenic endothelium.","authors":"Soo-Been Jeon, Hyebin Koh, A-Reum Han, Jieun Kim, Sunghun Lee, Jae-Ho Lee, Seung-Soon Im, Young-Sup Yoon, Jong-Hee Lee, Ji Yoon Lee","doi":"10.1038/s41536-023-00320-4","DOIUrl":"10.1038/s41536-023-00320-4","url":null,"abstract":"<p><p>Red blood cell (RBC) generation from human pluripotent stem cells (PSCs) offers potential for innovative cell therapy in regenerative medicine as well as developmental studies. Ex vivo erythropoiesis from PSCs is currently limited by the low efficiency of functional RBCs with β-globin expression in culture systems. During induction of β-globin expression, the absence of a physiological microenvironment, such as a bone marrow niche, may impair cell maturation and lineage specification. Here, we describe a simple and reproducible culture system that can be used to generate erythroblasts with β-globin expression. We prepared a two-dimensional defined culture with ferric citrate treatment based on definitive hemogenic endothelium (HE). Floating erythroblasts derived from HE cells were primarily CD45⁺CD71⁺CD235a⁺ cells, and their number increased remarkably upon Fe treatment. Upon maturation, the erythroblasts cultured in the presence of ferric citrate showed high transcriptional levels of β-globin and enrichment of genes associated with heme synthesis and cell cycle regulation, indicating functionality. The rapid maturation of these erythroblasts into RBCs was observed when injected in vivo, suggesting the development of RBCs that were ready to grow. Hence, induction of β-globin expression may be explained by the effects of ferric citrate that promote cell maturation by binding with soluble transferrin and entering the cells.Taken together, upon treatment with Fe, erythroblasts showed advanced maturity with a high transcription of β-globin. These findings can help devise a stable protocol for the generation of clinically applicable RBCs.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"46"},"PeriodicalIF":7.2,"publicationDate":"2023-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10457393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10305990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineered inhaled nanocatalytic therapy for ischemic cerebrovascular disease by inducing autophagy of abnormal mitochondria.","authors":"Deping Wang, Bowen Li, Shuchao Wang, Yingjian Hao, Hua Wang, Wei Sun, Jimin Cao, Xin Zhou, Bin Zheng","doi":"10.1038/s41536-023-00315-1","DOIUrl":"10.1038/s41536-023-00315-1","url":null,"abstract":"<p><p>Mitochondrial dysfunction and subsequent accumulation of reactive oxygen species (ROS) are key contributors to the pathology of ischemic cerebrovascular disease. Therefore, elimination of ROS and damaged mitochondria is crucial for the effective treatment of this disease. For this purpose, we designed an inhalation nanotherapeutic agent, P/D@Mn/Co₃O₄, to treat ischemic cerebrovascular disease. Mn/Co₃O₄ effectively removed excess ROS from cells, reduced acute cellular oxidative stress, and protected neural cells from apoptosis. Furthermore, it depleted the H⁺ surrounding mitochondria and depolarized the mitochondrial membrane potential, inducing mitophagy and eliminating abnormal mitochondria, thereby avoiding the continuous overproduction of ROS by eliminating the source of ROS regeneration. On intranasal administration, Mn/Co₃O₄ encapsulated by platelet membranes and 2,3-(dioxy propyl)-trimethylammonium chloride can bypass the blood-brain barrier, enter the brain through the trigeminal and olfactory pathways, and target inflammatory regions to remove ROS and damaged mitochondria from the lesion area. In rat models of stroke and vascular dementia, P/D@Mn/Co₃O₄ effectively inhibited the symptoms of acute and chronic cerebral ischemia by scavenging ROS and damaged mitochondria in the affected area. Our findings indicate that the nanotherapeutic agent developed in this study can be used for the effective treatment of ischemic cerebrovascular disease.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"44"},"PeriodicalIF":7.2,"publicationDate":"2023-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10421937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10349894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transgene-free direct conversion of murine fibroblasts into functional muscle stem cells.","authors":"Xhem Qabrati, Inseon Kim, Adhideb Ghosh, Nicola Bundschuh, Falko Noé, Andrew S Palmer, Ori Bar-Nur","doi":"10.1038/s41536-023-00317-z","DOIUrl":"10.1038/s41536-023-00317-z","url":null,"abstract":"<p><p>Transcription factor-based cellular reprogramming provides an attractive approach to produce desired cell types for regenerative medicine purposes. Such cellular conversions are widely dependent on viral vectors to efficiently deliver and express defined factors in target cells. However, use of viral vectors is associated with unfavorable genomic integrations that can trigger deleterious molecular consequences, rendering this method a potential impediment to clinical applications. Here, we report on a highly efficient transgene-free approach to directly convert mouse fibroblasts into induced myogenic progenitor cells (iMPCs) by overexpression of synthetic MyoD-mRNA in concert with an enhanced small molecule cocktail. First, we performed a candidate compound screen and identified two molecules that enhance fibroblast reprogramming into iMPCs by suppression of the JNK and JAK/STAT pathways. Simultaneously, we developed an optimal transfection protocol to transiently overexpress synthetic MyoD-mRNA in fibroblasts. Combining these two techniques enabled robust and rapid reprogramming of fibroblasts into Pax7 positive iMPCs in as little as 10 days. Nascent transgene-free iMPCs proliferated extensively in vitro, expressed a suite of myogenic stem cell markers, and could differentiate into highly multinucleated and contractile myotubes. Furthermore, using global and single-cell transcriptome assays, we delineated gene expression changes associated with JNK and JAK/STAT pathway inhibition during reprogramming, and identified in iMPCs a Pax7⁺ stem cell subpopulation resembling satellite cells. Last, transgene-free iMPCs robustly engrafted skeletal muscles of a Duchenne muscular dystrophy mouse model, restoring dystrophin expression in hundreds of myofibers. In summary, this study reports on an improved and clinically safer approach to convert fibroblasts into myogenic stem cells that can efficiently contribute to muscle regeneration in vivo.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"43"},"PeriodicalIF":7.2,"publicationDate":"2023-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10409758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10325352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Correction: The bright side of fibroblasts: molecular signature and regenerative cues in major organs.","authors":"Rita N Gomes, Filipa Manuel, Diana S Nascimento","doi":"10.1038/s41536-023-00319-x","DOIUrl":"10.1038/s41536-023-00319-x","url":null,"abstract":"","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"42"},"PeriodicalIF":7.2,"publicationDate":"2023-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10406803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9965414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional ProTracer identifies patterns of cell proliferation in tissues and underlying regulatory mechanisms.","authors":"Xiuxiu Liu, Maoying Han, Wendong Weng, Yan Li, Wenjuan Pu, Kuo Liu, Xufeng Li, Lingjuan He, Ruilin Sun, Ruling Shen, Yulong He, Dandan Liang, Yi-Han Chen, Qing-Dong Wang, Jan S Tchorz, Bin Zhou","doi":"10.1038/s41536-023-00318-y","DOIUrl":"10.1038/s41536-023-00318-y","url":null,"abstract":"<p><p>A genetic system, ProTracer, has been recently developed to record cell proliferation in vivo. However, the ProTracer is initiated by an infrequently used recombinase Dre, which limits its broad application for functional studies employing floxed gene alleles. Here we generated Cre-activated functional ProTracer (fProTracer) mice, which enable simultaneous recording of cell proliferation and tissue-specific gene deletion, facilitating broad functional analysis of cell proliferation by any Cre driver.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"41"},"PeriodicalIF":7.2,"publicationDate":"2023-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10400583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9946025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A postnatal network of co-hepato/pancreatic stem/progenitors in the biliary trees of pigs and humans.","authors":"Wencheng Zhang, Xicheng Wang, Giacomo Lanzoni, Eliane Wauthier, Sean Simpson, Jennifer Ashley Ezzell, Amanda Allen, Carolyn Suitt, Jonah Krolik, Alexander Jhirad, Juan Dominguez-Bendala, Vincenzo Cardinale, Domenico Alvaro, Diletta Overi, Eugenio Gaudio, Praveen Sethupathy, Guido Carpino, Christopher Adin, Jorge A Piedrahita, Kyle Mathews, Zhiying He, Lola McAdams Reid","doi":"10.1038/s41536-023-00303-5","DOIUrl":"10.1038/s41536-023-00303-5","url":null,"abstract":"<p><p>A network of co-hepato/pancreatic stem/progenitors exists in pigs and humans in Brunner's Glands in the submucosa of the duodenum, in peribiliary glands (PBGs) of intrahepatic and extrahepatic biliary trees, and in pancreatic duct glands (PDGs) of intrapancreatic biliary trees, collectively supporting hepatic and pancreatic regeneration postnatally. The network is found in humans postnatally throughout life and, so far, has been demonstrated in pigs postnatally at least through to young adulthood. These stem/progenitors in vivo in pigs are in highest numbers in Brunner's Glands and in PDGs nearest the duodenum, and in humans are in Brunner's Glands and in PBGs in the hepato/pancreatic common duct, a duct missing postnatally in pigs. Elsewhere in PDGs in pigs and in all PDGs in humans are only committed unipotent or bipotent progenitors. Stem/progenitors have genetic signatures in liver/pancreas-related RNA-seq data based on correlation, hierarchical clustering, differential gene expression and principal component analyses (PCA). Gene expression includes representative traits of pluripotency genes (SOX2, OCT4), endodermal transcription factors (e.g. SOX9, SOX17, PDX1), other stem cell traits (e.g. NCAM, CD44, sodium iodide symporter or NIS), and proliferation biomarkers (Ki67). Hepato/pancreatic multipotentiality was demonstrated by the stem/progenitors' responses under distinct ex vivo conditions or in vivo when patch grafted as organoids onto the liver versus the pancreas. Therefore, pigs are logical hosts for translational/preclinical studies for cell therapies with these stem/progenitors for hepatic and pancreatic dysfunctions.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"40"},"PeriodicalIF":7.2,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10394089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10158115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}