The progress of tissue-engineering technology has realized development of new therapies to treat various disorders by using cultured cells. Cell-and tissue-based therapies have been successfully applied to human patie...The progress of tissue-engineering technology has realized development of new therapies to treat various disorders by using cultured cells. Cell-and tissue-based therapies have been successfully applied to human patients, and several tissue-engineered products have been approved by the regulatory agencies and are commercially available. In the review article, we describe our experience of development and clinical application of cell sheet-based regenerative medicine.Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) have been shown to be useful for removal of gastrointestinal neoplasms with less invasiveness compared with open surgery, especially in esophageal surgery. However, postoperative inflammation and stenosis are major complications observed after intensive mucosal resection. Therefore, we have developed novel regenerative medicine to prevent such complications and promote wound healing of esophageal mucosa after EMR or ESD. Transplantable oral mucosal epithelial cell sheets were fabricated from patients' own oral mucosa. Immediately after EMR or ESD, fabricated autologous cell sheets were endoscopically transplanted to the ulcer sites. We performed a preclinical study with a canine model. In human clinical settings, cell culture and cell sheet fabrication were performed in clean rooms according to good manufacturing practice guidelines, and pharmaceutical drugs were used as supplements to culture medium in place of research regents used in animal study. We believe that cell-based regenerative medicine would be useful to improve quality of life of patients after EMR or ESD.展开更多
Background:Tumors possess incessant growth features,and expansion of their masses demands sufficient oxygen supply by red blood cells(RBCs).In adult mammals,the bone marrow(BM)is the main organ regulating hematopoiesi...Background:Tumors possess incessant growth features,and expansion of their masses demands sufficient oxygen supply by red blood cells(RBCs).In adult mammals,the bone marrow(BM)is the main organ regulating hematopoiesis with dedicated manners.Other than BM,extramedullary hematopoiesis is discovered in various pathophysiological settings.However,whether tumors can contribute to hematopoiesis is completely unknown.Accumulating evidence shows that,in the tumor microenvironment(TME),perivascular localized cells retain progenitor cell properties and can differentiate into other cells.Here,we sought to better understand whether and how perivascular localized pericytes in tumors manipulate hematopoiesis.Methods:To test if vascular cells can differentiate into RBCs,genome-wide expression profiling was performed using mouse-derived pericytes.Genetic tracing of perivascular localized cells employing NG2-CreERT2:R26R-tdTomato mouse strain was used to validate the findings in vivo.Fluorescence-activated cell sorting(FACS),single-cell sequencing,and colony formation assays were applied for biological studies.The production of erythroid differentiationspecific cytokine,erythropoietin(EPO),in TME was checked using quantitative polymerase chain reaction(qPCR),enzyme-linked immunosorbent assay(ELISA,magnetic-activated cell sorting and immunohistochemistry.To investigate BM function in tumor erythropoiesis,BM transplantation mouse models were employed.Results:Genome-wide expression profiling showed that in response to plateletderived growth factor subunit B(PDGF-B),neural/glial antigen 2(NG2)+perivascular localized cells exhibited hematopoietic stem and progenitor-like features and underwent differentiation towards the erythroid lineage.PDGF-B simultaneously targeted cancer-associated fibroblasts to produce high levels of EPO,a crucial hormone that necessitates erythropoiesis.FACS analysis using genetic tracing of NG2+cells in tumors defined the perivascular localized cell-derived subpopulation of hematopoietic cells.Single-cell sequencing and colony formation assays validated the fact that,upon PDGF-B stimulation,NG2+cells isolated from tumors acted as erythroblast progenitor cells,which were distinctive from the canonical BM hematopoietic stem cells.Conclusions:Our data provide a new concept of hematopoiesis within tumor tissues and novel mechanistic insights into perivascular localized cell-derived erythroid cells within TME.Targeting tumor hematopoiesis is a novel therapeutic concept for treating various cancers that may have profound impacts on cancer therapy.展开更多
Advanced driver assistance systems, especially autonomous emergency braking and forward collision warnings, have becomepopular in Japan. To reduce the number of road traffic accidents, safety information should be pro...Advanced driver assistance systems, especially autonomous emergency braking and forward collision warnings, have becomepopular in Japan. To reduce the number of road traffic accidents, safety information should be provided to a driver earlier thanavoidance or warning messages so as to avoid a risky situation. A series of actual running tests was conducted to evaluate theactivation timing and effectiveness of awareness messages. Objective analysis showed that the drivers could avoid an obstaclewith a sufficient safety margin thanks to any of the awareness messages. Subjective ratings showed that the best timing is 10 sbefore encountering the obstacle. The results of objective analysis are limited in the present paper, and further analyses arerequired.展开更多
基金CAMS Innovation Fund for Medical Sciences(2021‐I2M‐1‐017),the National Natural Science Foundation of China(81970107),State Key Laboratory of Experimental Hematology Research Grant(Z22‐02)和Tianjin“131”Science Fund for Creative Research Groups(2021)基金支持Yihai Cao获得the Swed is h Research Counc i l(2016‐02215,2019‐01502,2020‐06121,2021‐06122),National Key R&D Program of China(2020YFC0846600)+6 种基金the Hong Kong Centre for Cerebro‐cardiovascular Health Engineering,the Swedish Cancer Foundation(200734PjF),the Swedish Children's Cancer Foundation(PR2018‐0107)the Strategic Research Areas(SFO)‐Stem Cell and Regenerative Medicine Foundation,the Karolinska Institute Foundation(2020‐02080)the Karolinska Institute distinguished professor award,and the Karolinska Institute Foundation(2020‐02588)基金支持Kayoko Hosaka获得the Karolinska Institute Foundation基金支持Takahiro Seki获得the Scandinavia‐Japan Sasakawa Foundation基金支持Xu Jing获得the National Natural Science Foundation of China(81801163)and Doctor Fund of Shandong Natural Science Foundation(ZR201807060846)基金支持Masahito Yoshihara获得the Japan Society for the Promotion of Science(JSPS)Overseas Research Fellowships基金支持。
基金Supported by The Formation of Innovation Center for Fusion of Advanced Technologies in the Special Coordination Funds for Promoting ScienceTechnology from the Ministry of Education, Culture, Sports, Science, and Technology, Japan
文摘The progress of tissue-engineering technology has realized development of new therapies to treat various disorders by using cultured cells. Cell-and tissue-based therapies have been successfully applied to human patients, and several tissue-engineered products have been approved by the regulatory agencies and are commercially available. In the review article, we describe our experience of development and clinical application of cell sheet-based regenerative medicine.Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) have been shown to be useful for removal of gastrointestinal neoplasms with less invasiveness compared with open surgery, especially in esophageal surgery. However, postoperative inflammation and stenosis are major complications observed after intensive mucosal resection. Therefore, we have developed novel regenerative medicine to prevent such complications and promote wound healing of esophageal mucosa after EMR or ESD. Transplantable oral mucosal epithelial cell sheets were fabricated from patients' own oral mucosa. Immediately after EMR or ESD, fabricated autologous cell sheets were endoscopically transplanted to the ulcer sites. We performed a preclinical study with a canine model. In human clinical settings, cell culture and cell sheet fabrication were performed in clean rooms according to good manufacturing practice guidelines, and pharmaceutical drugs were used as supplements to culture medium in place of research regents used in animal study. We believe that cell-based regenerative medicine would be useful to improve quality of life of patients after EMR or ESD.
基金CAMS Innovation Fund for Medical Sciences,Grant/Award Number:2021-I2M-1-017National Natural Science Foundation of China,Grant/Award Number:81970107+12 种基金State Key Laboratory of Experimental Hematology Research,Grant/Award Number:Z22-02Tianjin“131”Science Fund for Creative Research Groups,Grant/Award Number:2021Swedish Research Council,Grant/Award Numbers:2016-02215,2019-01502,2020-06121,2021-06122National Key R&D Program of China,Grant/Award Number:2020YFC0846600Hong Kong Centre for Cerebro-cardiovascular Health EngineeringSwedish Cancer Foundation,Grant/Award Number:200734PjFSwedish Children’s Cancer Foundation,Grant/Award Number:PR2018-0107Strategic Research Areas(SFO)-Stem Cell and Regenerative Medicine FoundationKarolinska Institute distinguished professor awardKarolinska Institute FoundationScandinavia-Japan Sasakawa Foundation,Grant/Award Number:81801163Doctor Fund of Shandong Natural Science Foundation,Grant/Award Number:ZR201807060846Japan Society for the Promotion of Science(JSPS)Overseas Research Fellowships。
文摘Background:Tumors possess incessant growth features,and expansion of their masses demands sufficient oxygen supply by red blood cells(RBCs).In adult mammals,the bone marrow(BM)is the main organ regulating hematopoiesis with dedicated manners.Other than BM,extramedullary hematopoiesis is discovered in various pathophysiological settings.However,whether tumors can contribute to hematopoiesis is completely unknown.Accumulating evidence shows that,in the tumor microenvironment(TME),perivascular localized cells retain progenitor cell properties and can differentiate into other cells.Here,we sought to better understand whether and how perivascular localized pericytes in tumors manipulate hematopoiesis.Methods:To test if vascular cells can differentiate into RBCs,genome-wide expression profiling was performed using mouse-derived pericytes.Genetic tracing of perivascular localized cells employing NG2-CreERT2:R26R-tdTomato mouse strain was used to validate the findings in vivo.Fluorescence-activated cell sorting(FACS),single-cell sequencing,and colony formation assays were applied for biological studies.The production of erythroid differentiationspecific cytokine,erythropoietin(EPO),in TME was checked using quantitative polymerase chain reaction(qPCR),enzyme-linked immunosorbent assay(ELISA,magnetic-activated cell sorting and immunohistochemistry.To investigate BM function in tumor erythropoiesis,BM transplantation mouse models were employed.Results:Genome-wide expression profiling showed that in response to plateletderived growth factor subunit B(PDGF-B),neural/glial antigen 2(NG2)+perivascular localized cells exhibited hematopoietic stem and progenitor-like features and underwent differentiation towards the erythroid lineage.PDGF-B simultaneously targeted cancer-associated fibroblasts to produce high levels of EPO,a crucial hormone that necessitates erythropoiesis.FACS analysis using genetic tracing of NG2+cells in tumors defined the perivascular localized cell-derived subpopulation of hematopoietic cells.Single-cell sequencing and colony formation assays validated the fact that,upon PDGF-B stimulation,NG2+cells isolated from tumors acted as erythroblast progenitor cells,which were distinctive from the canonical BM hematopoietic stem cells.Conclusions:Our data provide a new concept of hematopoiesis within tumor tissues and novel mechanistic insights into perivascular localized cell-derived erythroid cells within TME.Targeting tumor hematopoiesis is a novel therapeutic concept for treating various cancers that may have profound impacts on cancer therapy.
文摘Advanced driver assistance systems, especially autonomous emergency braking and forward collision warnings, have becomepopular in Japan. To reduce the number of road traffic accidents, safety information should be provided to a driver earlier thanavoidance or warning messages so as to avoid a risky situation. A series of actual running tests was conducted to evaluate theactivation timing and effectiveness of awareness messages. Objective analysis showed that the drivers could avoid an obstaclewith a sufficient safety margin thanks to any of the awareness messages. Subjective ratings showed that the best timing is 10 sbefore encountering the obstacle. The results of objective analysis are limited in the present paper, and further analyses arerequired.