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The evolving roles of Wnt signaling in stem cell proliferation and differentiation, the development of human diseases, and therapeutic opportunities

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Genes & Diseases 2024年第3期11卷 155-187页

作者： michael Yu Kevin Qin jiaming Fan Guozhi Zhao Piao Zhao Wei Zeng Connie Chen Annie Wang Yonghui Wang jiamin Zhong Yi Zhu William Wagstaff Rex C.haydon Hue H.Luu Sherwin Ho michael j.Lee jason Strelzow Russell R.Reid Tong-Chuan He School of Medicine Rosalind Franklin University of Medicine and ScienceNorth ChicagoIL 60064USA Molecular Oncology Laboratory Department of Orthopedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Ministry of Education Key Laboratory of Diagnostic Medicine and Department of Clinical BiochemistryThe School of Laboratory MedicineChongqing Medical UniversityChongqing 400016China Department of Orthopedic Surgery The First Affliated Hospital of Chongqing Medical UniversityChongqing 400016China Department of Urology The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Department of Clinical Laboratory Medicine Shanghai Jiaotong University School of MedicineShanghai 200000China Department of Orthopaedic Surgery Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China Laboratory of Craniofacial Suture Biology and Development Department of Surgery Section of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA Department of Neurology The First Dongguan Affiliated HospitalGuangdong Medical UniversityDongguanGuangdong 523475China

The evolutionarily conserved Wnt signaling pathway plays a central role in develop-ment and adult tissue homeostasis across species.Wnt proteins are secreted,lipid-modified signaling molecules that activate the canonical(β-catenin dependent)and non-canonical(β-catenin independent)Wnt signaling pathways.Cellular behaviors such as proliferation,differ-entiation,maturation,and proper body-axis specification are carried out by the canonical pathway,which is the best characterized of the known Wnt signaling paths.Wnt signaling has emerged as an important factor in stem cell biology and is known to affect the self-renewal of stem cells in various tissues.This includes but is not limited to embryonic,hematopoietic,mesenchymal,gut,neural,and epidermal stem cells.Wnt signaling has also been implicated in tumor cells that exhibit stem cell-like properties.Wnt signaling is crucial for bone formation and presents a potential target for the development of therapeutics for bone disorders.Not surprisingly,aberrant Wnt signaling is also associated with a wide variety of diseases,including cancer.Mutations of Wnt pathway members in cancer can lead to unchecked cell proliferation,epithelial-mesenchymal transition,and metastasis.Altogether,advances in the understand-ing of dysregulated Wnt signaling in disease have paved the way for the development of novel therapeutics that target components of the Wnt pathway.Beginning with a brief overview of the mechanisms of canonical and non-canonical Wnt,this review aims to summarize the cur-rent knowledge of Wnt signaling in stem cells,aberrations to the Wnt pathway associated with diseases,and novel therapeutics targeting the Wnt pathway in preclinical and clinical studies.

关键词： β-Catenin Cancer Canonical Wnt Disease Non-canonical Wnt Stem cells Targeted therapy Wnt signaling

SV40 large T antigen-induced immortalization reprograms mouse cardiomyocyte progenitors with mesenchymal stem cell characteristics and osteogenic potential

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Genes & Diseases 2023年第4期10卷 1161-1164页

作者： Yichun Yu jiamin Zhong Connie Chen Yannian Gou Guozhi Zhao Piao Zhao Yonghui Wang Wei Zeng Annie Wang William D.Wagstaff jr Rex C.haydon Tong-Chuan He Russell R.Reid michael j.Lee Hue H.Luu jiaming Fan Emergency Department Beijing Hospitaland The National Center of GerontologyInstitute of Geriatric MedicineChinese Academy of Medical SciencesBeijing 100051China Molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Ministry of Education Key Laboratory of Diagnostic Medicine and the School of Laboratory Diagnostic MedicineChongqing Medical UniversityChongqing 400016China Departments of Orthopaedic Surgery and Urology The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Department of Clinical Laboratory Medicine Shanghai Jiaotong University School of MedicineShanghai 200025China Department of Neurology The Second Affiliated Hospital of Jianghan UniversityWuhanHubei 430050China Laboratory of Craniofacial Suture Biology and Development Department of Surgery Section of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA

While progenitor cell-based cardiomyocyte regeneration holds great promise of repairing an injured heart,primary cardiomyogenic progenitors(CPs)have a limited life span in culture,hampering the use of CPs for in vitro and in vivo studies.We previously isolated primary CPs from mouse E15.5 fetal heart,and reversibly immortalized them with SV40 large T antigen(SV40 LTA),resulting in immortalized CPs(iCPs),which maintain long-term proliferation and ex-press cardiomyogenic markers and retain differentiation potential under appropriate differentiation conditions.

关键词： progenitor cardio potential

Bone Morphogenic Protein 9(BMP9)/Growth Differentiation Factor 2(GDF2)modulates mouse adult hippocampal neurogenesis by regulating the survival of early neural progenitors

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Genes & Diseases 2023年第4期10卷 1175-1179页

作者： Mary Rose Rogers Wei Zeng Xian Zhang Ruidong Li Qiang Wei Yuhan Kong Piao Zhao Guozhi Zhao Yonghui Wang jiamin Zhong Yi Zhu Rex C.haydon Hue H.Luu Russell R.Reid Daniel A.Peterson michael j.Lee Tong-Chuan He Molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Graduate Program Committee on Genetics Genomics and System BiologyThe University of ChicagoChicagoIL 60637USA Department of Interventional Neurology The First Dongguan Affiliated HospitalGuangdong Medical UniversityDongguanGuangdong 523475China Department of Neurology The Second Affiliated Hospital of Jianghan UniversityWuhanHubei 430000China Department of Orthopaedic Surgery The Second Affiliated Hospital of Chongqing Medical UniversityChongqing 400010China Department of Clinical Laboratory Medicine Rehabilitation MedicineOrthopaedic Surgery and UrologyThe First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Department of Endocrinology Shanghai Jiao-Tong University School of MedicineShanghai 200000China Ministry of Education Key Laboratory of Diagnostic Medicine and Department of Clinical BiochemistryThe School of Laboratory MedicineChongqing Medical UniversityChongqing 400016China Department of Orthopaedic Surgery Beijing HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China Laboratory of Craniofacial Suture Biology and Development Department of Surgery Section of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA Center for Stem Cell and Regenerative Medicine Rosalind Franklin University of Medicine and ScienceNorth ChicagoIL 60064USA

Adult neurogenesis occurs in two specialized regions of the mammalian brain,the subventricular zone(SVZ)and the subgranular zone(SGZ)of the dentate gyrus(DG).^(1)Adult hippocampal neural stem cells(NSCs),referred to as Type 1 cells represented by radial glia-like cells(RGLs),generate Type 2 cells that are divided into Type 2a and Type 2 b subpopulations,the latter of which give rise to Type 3 cells(neuroblasts).

关键词： neural progenitor ventricular

Beyond the liver in patients with non-alcoholic fatty liver disease (NAFLD)——cause for concern?

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Hepatobiliary Surgery and Nutrition 2018年第2期7卷 138-142页

作者： Matthew j.Armstrong Geoffrey haydon Wing-Kin Syn Liver Unit Queen Elizabeth University Hospital BirminghamBirminghamUK Centre for Liver Research NIHR Biomedical Research CentreUniversity of BirminghamBirminghamUK Section of Gastroenterology Ralph H Johnson Veterans Affairs Medical CenterCharlestonSouth CarolinaUSA Division of Gastroenterology and Hepatology Department of MedicineMedical University of South CarolinaCharlestonSouth CarolinaUSA

Non-alcoholic fatty liver disease(NAFLD)is a global public health problem and is the most common cause of chronic liver disease worldwide.The prevalence of NAFLD is approximately 30%,irrespective of ethnicity,and parallels the exponential rise of the obesity and diabetes epidemics.The active inflammatory and cell injury component of NAFLD,known as non-alcoholic steatohepatitis(NASH),increases the risk of liver-related mortality by 5 to 10 times;but this is largely dependent on the extent of fibrosis(1,2).Despite this,cardiovascular disease(CVD)and extra-hepatic malignancy remain the commonest causes of death in these cohorts.Therefore,non-surprisingly the last decade has seen the clinical focus switch from NAFLD as a solitary organ entity to a multi-systemic disease.

关键词： NAFLD liver mortality

Melanoma:Molecular genetics,metastasis,targeted therapies,immunotherapies,and therapeutic resistance

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Genes & Diseases 2022年第6期9卷 1608-1623页

作者： William Wagstaff Rimel N.Mwamba Karina Grullon Mikhayla Armstrong Piao Zhao Bryce Hendren-Santiago Kevin H.Qin Alexander j.Li Daniel A.Hu Andrew Youssef Russell R.Reid Hue H.Luu Le Shen Tong-Chuan He Rex C.haydon The Pritzker School of Medicine and the Medical Scientist Training ProgramThe University of Chicago Medical CenterChicagoIL 60637USA Molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Department of Orthopaedic Surgery The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016PR China Laboratory of Craniofacial Suture Biology and Development Department of Surgery Section of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA Department of Surgery The University of Chicago Medical CenterChicagoIL 60637USA

Cutaneous melanoma is a common cancer and cases have steadily increased since the mid 70s.For some patients,early diagnosis and surgical removal of melanomas is lifesaving,while other patients typically turn to molecular targeted therapies and immunotherapies as treatment options.Easy sampling of melanomas allows the scientific community to identify the most prevalent mutations that initiate melanoma such as the BRAF,NRAS,and TERT genes,some of which can be therapeutically targeted.Though initially effective,many tumors acquire resistance to the targeted therapies demonstrating the need to investigate compensatory pathways.Immunotherapies represent an alternative to molecular targeted therapies.However,inter-tumoral immune cell populations dictate initial therapeutic response and even tumors that responded to treatment develop resistance in the long term.As the protocol for combination therapies develop,so will our scientific understanding of the many pathways at play in the progression of melanoma.The future direction of the field may be to find a molecule that connects all of the pathways.Meanwhile,noncoding RNAs have been shown to play important roles in melanoma development and progression.Studying noncoding RNAs may help us to understand how resistance e both primary and acquired e develops;ultimately allow us to harness the true potential of current therapies.This review will cover the basic structure of the skin,the mutations and pathways responsible for transforming melanocytes into melanomas,the process by which melanomas metastasize,targeted therapeutics,and the potential that noncoding RNAs have as a prognostic and treatment tool.

关键词： BRAF inhibitors Checkpoint inhibitors Drug resistance Immunotherapy Melanoma Melanoma metastasis Skin cancer Targeted therapy Therapeutic resistance

The versatile functions of Sox9 in development,stem cells,and human diseases

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Genes & Diseases 2014年第2期1卷 149-161页

作者： Alice jo Sahitya Denduluri Bosi Zhang Zhongliang Wang Liangjun Yin Zhengjian Yan Richard Kang Lewis L.Shi james Mok michael j.Lee Rex C.haydon Molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Departments of Orthopaedic Surgery The Affiliated Hospitals of Chongqing Medical UniversityChongqing 400046China

The transcription factor Sox9 was first discovered in patients with campomelic dysplasia,a haploinsufficiency disorder with skeletal deformities caused by dysregulation of Sox9 expression during chondrogenesis.Since then,its role as a cell fate determiner during embryonic development has been well characterized;Sox9 expression differentiates cells derived from all three germ layers into a large variety of specialized tissues and organs.However,recent data has shown that ectoderm-and endoderm-derived tissues continue to express Sox9 in mature organs and stem cell pools,suggesting its role in cell maintenance and specification during adult life.The versatility of Sox9 may be explained by a combination of posttranscriptional modifications,binding partners,and the tissue type in which it is expressed.Considering its importance during both development and adult life,it follows that dysregulation of Sox9 has been implicated in various congenital and acquired diseases,including fibrosis and cancer.This review provides a summary of the various roles of Sox9 in cell fate specification,stem cell biology,and related human diseases.Ultimately,understanding the mechanisms that regulate Sox9 will be crucial for developing effective therapies to treat disease caused by stem cell dysregulation or even reverse organ damage.

关键词： Development Sox9 Stem cells Transcription factor

Corrigendum to “Characterization of the essential role of bone morphogenetic protein 9 (BMP9) in osteogenic differentiation of mesenchymal stem cells (MSCs) through RNA interference” [Genes & Diseases 5(2018):172–184]

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Genes & Diseases 2023年第2期10卷 632-637页

作者： Shujuan Yan Ruyi Zhang Ke Wu jing Cui Shifeng Huang Xiaojuan ji Liping An Chengfu Yuan Cheng Gong Linghuan Zhang Wei Liu Yixiao Feng Bo Zhang Zhengyu Dai Yi Shen Xi Wang Wenping Luo Bo Liu Rex C. haydon michael j. Lee Russell R. Reid jennifer Moriatis Wolf Qiong Shi Hue H. Luu Tong-Chuan He Yaguang Weng Ministry of Education Key Laboratory of Diagnostic Medicine and School of Laboratory Medicine Chongqing Medical UniversityChongqing 400016China Molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA The School of Pharmacy and the Affiliated Hospitals of Chongqing Medical University Chongqing 400016China Key Laboratory of Orthopaedic Surgery of Gansu Province and the Department of Orthopaedic Surgery The Second Hospital of Lanzhou UniversityLanzhouGansu 730030China Department of Biochemistry and Molecular Biology China Three Gorges University School of MedicineYichangHubei 443002China Department of Surgery The Affiliated Zhongnan Hospital of Wuhan UniversityWuhanHubei 430071China Department of Orthopaedic Surgery Chongqing Hospital of Traditional Chinese MedicineChongqing 400021China Department of Orthopaedic Surgery Xiangya Second Hospital of Central South UniversityChangshaHunan 410011China Department of Surgery Laboratory of Craniofacial Biology and DevelopmentSection of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA

The authors regret having several image assembly errors.Specifically,in Figure 3A panel b,the image for "AdsimB9-4 only"group was erroneously duplicated with an overlapping image from the"AdRFp"group;and the image for"AdsimB9-1+BMP9"groupwas erroneouslyduplicatedwithan overlapping image from"AdsimB9-8+BMP9"group.In Figure 4Apanel a,the images for"BMP9"group and "BMP9+simB9-4"group were erroneously duplicated with an overlapping image from"simB9-4"group.In Figure 5A,the image for"BMP9+simB9-4/Day3"group was erroneously duplicated with an overlapping image from"BMP9+simB9-7/Day3"group;and the image for"BMP9+simB9-4/Day5"group was erroneously duplicated with an overlapping image from an unrelated experiment.In Figure 6B,the image for"BMP9+simB9-7/Day 11"group was erroneously duplicated with an overlapping image from the"BMP9+simB9-4/Day 11"group.

关键词： Figure BMP9 Cor

Ferroptosis as a novel form of regulated cell death:Implications in the pathogenesis,oncometabolism and treatment of human cancer

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Genes & Diseases 2022年第2期9卷 347-357页

作者： Feifei Pu Fengxia Chen Zhicai Zhang Deyao Shi Binlong Zhong Xiao Lv Andrew Blake Tucker jiaming Fan Alexander j.Li Kevin Qin Daniel Hu Connie Chen Hao Wang Fang He Na Ni Linjuan Huang Qing Liu William Wagstaff Hue H.Luu Rex C.haydon Le Shen Tong-Chuan He jianxiang Liu Zengwu Shao Department of Orthopedics Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430022PR China Department of Radiation and Medical Oncology Zhongnan HospitalWuhan UniversityWuhanHubei 430071PR China Hubei Cancer Clinical Study Center Zhongnan HospitalWuhan UniversityWuhanHubei 430071PR China Department of Orthopaedic Surgery Johns Hopkins UniversityBaltimoreMD 21205USA Molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Ministry of Education Key Laboratory of Diagnostic Medicine Department of Clinical BiochemistrySchool of Laboratory MedicineChongqing Medical UniversityChongqing 400016PR China Departments of Nephrology and Obstetrics and GynecologyThe First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016PR China Department of Spine Surgery Second Xiangya HospitalCentral South UniversityChangshaHunan 410011PR China Department of Surgery The University of Chicago Medical CenterChicagoIL 60637USA

The treatment of cancer mainly involves surgical excision supplemented by radiotherapy and chemotherapy.Chemotherapy drugs act by interfering with tumor growth and inducing the death of cancer cells.Anti-tumor drugs were developed to induce apoptosis,but some patient’s show apoptosis escape and chemotherapy resistance.Therefore,other forms of cell death that can overcome the resistance of tumor cells are important in the context of cancer treatment.Ferroptosis is a newly discovered iron-dependent,non-apoptotic type of cell death that is highly negatively correlated with cancer development.Ferroptosis is mainly caused by the abnormal increase in iron-dependent lipid reactive oxygen species and the imbalance of redox homeostasis.This review summarizes the progression and regulatory mechanism of ferroptosis in cancer and discusses its possible clinical applications in cancer diagnosis and treatment.

关键词： Cancer Cancer therapy Clinical application Ferroptosis Lipid peroxidation Pathogenesis

Bone Morphogenetic Protein (BMP) signaling in development and human diseases

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Genes & Diseases 2014年第1期1卷 87-105页

作者： Richard N.Wang jordan Green Zhongliang Wang Youlin Deng Min Qiao michael Peabody Qian Zhang jixing Ye Zhengjian Yan Sahitya Denduluri Olumuyiwa Idowu Melissa Li Christine Shen Alan Hu Rex C.haydon Richard Kang james Mok michael j.Lee Hue L.Luu Lewis L.Shi The University of Chicago Pritzker School of Medicine ChicagoIL 60637USA Molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Departments of Orthopaedic Surgery Medicineand Gynecologythe Affiliated Hospitals of Chongqing Medical UniversityChongqing 400016China School of Bioengineering Chongqing UniversityChongqingChina

Bone Morphogenetic Proteins(BMPs)are a group of signaling molecules that belongs to the Transforming Growth Factor-b(TGF-b)superfamily of proteins.Initially discovered for their ability to induce bone formation,BMPs are now known to play crucial roles in all organ systems.BMPs are important in embryogenesis and development,and also in maintenance of adult tissue homeostasis.Mouse knockout models of various components of the BMP signaling pathway result in embryonic lethality or marked defects,highlighting the essential functions of BMPs.In this review,we first outline the basic aspects of BMP signaling and then focus on genetically manipulated mouse knockout models that have helped elucidate the role of BMPs in development.A significant portion of this review is devoted to the prominent human pathologies associated with dysregulated BMP signaling.

关键词： BMP signaling Development Genetics Mouse knockout Pathogenesis Signal transduction