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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

wnt signaling:Essential roles in osteoblast differentiation,bone metabolism and therapeutic implications for bone and skeletal disorders

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Genes & Diseases 2023年第4期10卷 1291-1317页

作者： Rexhina Vlashi Xingen Zhang Mengrui Wu Guiqian Chen College of Life Science and Medicine Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and BiomedicineZhejiang Sci-Tech UniversityHangzhouZhejiang 310018China Department of Orthopedics Jiaxing Key Laboratory for Minimally Invasive Surgery in Orthopaedics&Skeletal Regenerative MedicineZhejiang Rongjun HospitalJiaxingZhejiang 314001China Institute of Genetics College of Life ScienceZhejiang UniversityHangzhouZhejiang 310058China

wnt signaling executes an indispensable performance in osteoblast differentiation,bone development,homeostasis,and remodeling.wnt signals trigger the intracellular wnt signaling cascade to initiate regulating the implication of b-catenin in the bone environment.Going through the novel discoveries done via high-throughput sequencing technologies on ge-netic mouse models,we highlighted the significant contribution of wnt ligands,co-receptors,inhibitors,their related skeletal phenotypes in mouse models and the similar bone disorders clinically observed in human beings.Moreover,the crosstalk between wnt signaling pathway and BMP,TGF-b,FGF,Hippo,Hedgehog,Notch and PDGF signaling pathways is thoroughly demonstrated to be the underlying gene regulatory network that orchestrates osteoblast dif-ferentiation and bone development.We also introspected the significance of wnt signaling transduction in the reorganization of cellular metabolism by stimulating glycolysis,glutamine catabolism,and fatty acid oxidation in osteoblast-lineage cells that display an important reg-ulatory arbor in the cellular bioenergetics of the bone.Throughout this evaluation,most to date therapeutical approaches towards osteoporosis and other bone maladies found in human beings,are formulated with an aspiration to holistically revamp the present clinical applica-tions involving various monoclonal antibodies therapies that lack specificity,efficacy,and safety into more requisite advanced therapeutics that satisfy these three requirements for further clinical considerations.Conclusively,our review provides comprehensive scientific findings related to the fundamental significance of wnt signaling cascades in skeletal system and the underlying gene regulatory network with other signaling pathways enlightening re-searchers with the possibility to further integrate the identified target molecules into thera-peutic strategies for skeletal disorders treatment in the clinic.

关键词： Bone development Bone homeostasis Osteoblast differentiation Skeletal disorders wnt signaling

A novel decellularized matrix of wnt signaling-activated osteocytes accelerates the repair of critical-sized parietal bone defects with osteoclastogenesis, angiogenesis, and neurogenesis

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Bioactive Materials 2023年第3期21卷 110-128页

作者： Xiaofang Wang Yufei Ma Jie Chen Yujiao Liu Guangliang Liu Pengtao Wang Bo Wang Makoto M.Taketo Teresita Bellido Xiaolin Tu Laboratory of Skeletal Development and Regeneration Institute of Life SciencesChongqing Medical UniversityChongqing400016China Department of Pharmacology Graduate School of MedicineKyoto UniversityKyoto606-8501Japan Department of Physiology and Cell Biology University of Arkansas for Medical SciencesLittle RockAR72223USA Department of Anatomy and Cell Biology Indiana University School of MedicineIndianapolisIN46202USA

Cell source is the key to decellularized matrix(DM)strategy.This study compared 3 cell types,osteocytes with/without dominant active wnt/β-catenin signaling(daCO and WTO)and bone marrow stromal cells(BMSCs)for their DMs in bone repair.Decellularization removes all organelles and>95%DNA,and retained>74%collagen and>71%GAG,maintains the integrity of cell basement membrane with dense boundaries showing oval and honeycomb structure in osteocytic DM and smooth but irregular shape in the BMSC-DM.DM produced higher cell survival rate(90%)and higher proliferative activity.In vitro,daCO-DM induces more and longer stress fibers in BMSCs,conducive to cell adhesion,spreading,and osteogenic differentiation.8-wk after implantation of the critical-sized parietal bone defect model,daCO-DM formed tight structures,composed of a large number of densely-arranged type-I collagen under polarized light microscope,which is similar to and integrated with host bone.BV/TV(>54%)was 1.5,2.9,and 3.5 times of WTO-DM,BMSC-DM,and none-DM groups,and N.Ob/T.Ar(3.2×10^(2)/mm^(2))was 1.7,2.9,and 3.3 times.At 4-wk,daCO-DM induced osteoclastogenesis,2.3 times higher than WTO-DM;but BMSC-DM or none-DM didn't.daCO-DM increased the expression of RANKL and MCSF,Vegfa and Angpt1,and Ngf in BMSCs,which contributes to osteoclastogenesis,angiogenesis,and neurogenesis,respectively.daCO-DM promoted H-type vessel formation and nerve markersβ3-tubulin and NeuN expression.Conclusion:daCO-DM produces metabolic and neurovascularized organoid bone to accelerate the repair of bone defects.These features are expected to achieve the effect of autologous bone transplantation,suitable for transformation application.

关键词： Decellularized matrix Osteocyte wnt signaling 3D printing Regenerative repair Metabolic and neurovascular organoid bone

Induction of wnt signaling antagonists and p21-activated kinase enhances cardiomyocyte proliferation during zebrafish heart regeneration

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Journal of Molecular Cell Biology 2021年第1期13卷 41-58页

作者： Xiangwen Peng Kaa Seng Lai Peilu She Junsu Kang Tingting Wang Guobao Li Yating Zhou jianjian Sun Daqing Jin Xiaolei Xu Lujian Liao Jiandong Liu Ethan Lee Kenneth D.Poss Tao P.Zhong State Key Laboratory of Genetic Engineering School of Life SciencesZhong Shan HospitalFudan UniversityShanghai 200438China Shanghai Key Laboratory of Regulatory Biology Institute of Molecular MedicineEast China Normal University School of Life SciencesShanghai 200241China Department of Cell Biology Duke University Medical CenterDurhamNC 27710USA Department of Biochemistry and Molecular Biology Mayo ClinicRochesterMN 55905USA Department of Pathology and Laboratory Medicine McAllister Heart InstituteUniversity of North Carolina at Chapel HillChapel HillNC 27599USA Department of Developmental and Cell Biology Vanderbilt University School of MedicineNashvilleTN 37232USA T These authors share first authorship.

Heart regeneration occurs by dedifferentiation and proliferation of pre-existing cardiomyocytes(CMs).However,the signaling mechanisms by which injury induces CM renewal remain incompletely understood.Here,we find that cardiac injury in zebrafish induces expression of the secreted wnt inhibitors,including Dickkopf 1(Dkkl),Dkk3,secreted Frizzled-related protein 1(sFrpl),and sFrp2,in cardiac tissue adjacent to injury sites.Experimental blocking of wnt activity via Dkkl overexpression enhances CM proliferation and heart regeneration,whereas ectopic activation of wnt8 signaling blunts injury-induced CM dedifferentiation and proliferation.Although wnt signaling is dampened upon injury,the cytoplasmic β-catenin is unexpectedly increased at disarrayed CM sarcomeres in myocardial wound edges.Our analyses indicated that p21-activated kinase 2(Pak2)is induced at regenerating CMs,where it phosphorylates cytoplasmic β-catenin at Ser 675 and increases its stability at disassembled sarcomeres.Myocardial-specific induction of the phospho-mimeticβ-catenin(S675E)enhances CM dedifferentiation and sarcomere disassembly in response to injury.Conversely,inactivation of Pak2 kinase activity reduces the Ser 675-phosphorylatedβ-catenin(pS675-β-catenin)and attenuates CM sarcomere disorganization and dedifferentiation・Taken together,these findings demonstrate that coordination of wnt signaling inhibition and Pak2/pS675-βYatenin signaling enhances zebrafish heart regeneration by supporting CM dedifferentiation and proliferation.

关键词： heart regeneration wnt signaling PAK2 kinase cardiomyocyte proliferation cardiomyocyte dedifferentiation zebrafish

New insights into the regulation of Axin function in canonical wnt signaling pathway

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Protein & Cell 2014年第3期5卷 186-193页

作者： Xiaomin Song Sheng Wang Lin Li State Key Laboratory of Molecular Biology Institute of Biochemistry and Cell Biology Shanghai Institutes for BiologicalSciences Chinese Academy of Sciences Shanghai 200031 China

The wnt signaling pathway plays crucial roles during embryonic development, whose aberration is implicated in a variety of human cancers. Axin, a key component of canonical wnt pathway, plays dual roles in modulat- ing wnt signaling： on one hand, Axin scaffolds the ＂l^-catenin destruction complex＂ to promote 13-catenin degradation and therefore inhibits the wnt signal transduction; on the other hand, Axin interacts with LRP5/6 and facilitates the recruitment of GSK3 to the plasma membrane to promote LRP516 phosphorylation and wnt signaling. The differential assemblies of Axin with these two distinct complexes have to be tightly controlled for appropriate transduction of the ＂on＂ or ＂off＂ wnt signal. So far, there are multiple mechanisms revealed in the regulation of Axin activity, such as post- transcriptional modulation, homo/hetero-polymerization and auto-inhibition. These mechanisms may work cooperatively to modulate the function of Axin, thereby playing an important role in controlling the canonical wnt signaling. In this review, we will focus on the recent progresses regarding the regulation of Axin function in canonical wnt signaling.

关键词： wnt signaling Axin post-transcriptionalmodification polymerization auto-inhibition

Loss of canonical wnt signaling is involved in the pathogenesis of Alzheimer's disease

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Neural Regeneration Research 2018年第10期13卷 1705-1710页

作者： Cheril Tapia-Rojas Nibaldo C.Inestrosa Centro de Envejecimiento y Regeneración (CARE UC) Departamento de Biología Celular y MolecularFacultad de Ciencias BiológicasPontificia Universidad Católica de Chile Centre for Healthy Brain Ageing School of PsychiatryFaculty of MedicineUniversity of New South Wales Centro de Excelencia en Biomedicina de Magallanes (CEBIMA) Universidad de Magallanes

Alzheimer＇s disease（AD） is the most common form of dementia in the older population, however, the precise cause of the disease is unknown. The neuropathology is characterized by the presence of aggregates formed by amyloid-β（Aβ） peptide and phosphorylated tau; which is accompanied by progressive impairment of memory. Diverse signaling pathways are linked to AD, and among these the wnt signaling pathway is becoming increasingly relevant, since it plays essential roles in the adult brain. Initially, wnt signaling activation was proposed as a neuroprotective mechanism against Aβ toxicity. Later, it was reported that it participates in tau phosphorylation and processes of learning and memory. Interestingly, in the last years we demonstrated that wnt signaling is fundamental in amyloid precursor protein（APP） processing and that wnt dysfunction results in Aβ production and aggregation in vitro. Recent in vivo studies reported that loss of canonical wnt signaling exacerbates amyloid deposition in a transgenic（Tg） mouse model of AD. Finally, we showed that inhibition of wnt signaling in a Tg mouse previously at the appearance of AD signs, resulted in memory loss, tau phosphorylation and Aβ formation and aggregation; indicating that wnt dysfunction accelerated the onset of AD. More importantly, wnt signaling loss promoted cognitive impairment, tau phosphorylation and Aβ1–42 production in the hippocampus of wild-type（WT） mice, contributing to the development of an Alzheimer＇s-like neurophatology. Therefore, in this review we highlight the importance of wnt/β-catenin signaling dysfunction in the onset of AD and propose that the loss of canonical wnt signaling is a triggering factor of AD.

关键词： wnt signaling wnt target genes wnt/β-catenin Alzheimer disease amyloid-β tau phosphorylation memory loss synaptic dysfunction

A growing field: the regulation of axonal regeneration by wnt signaling

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Neural Regeneration Research 2018年第1期13卷 43-52页

作者： Armando L. Garcia Adanna Udeh Karthik Kalahasty Abigail S. Hackam Bascom Palmer Eye Institute University of Miami Miller School of Medicine Miami FL USA

The canonical wnt/β-catenin pathway is a highly conserved signaling cascade that plays critical roles during embryogenesis. wnt ligands regulate axonal extension, growth cone guidance and synaptogenesis throughout the developing central nervous system （CNS）. Recently, studies in mammalian and fish model systems have demonstrated that wnt/β-catenin signaling also promotes axonal regeneration in the adult optic nerve and spinal cord after injury, raising the possibility that wnt could be developed as a therapeutic strategy. In this review, we summarize experimental evidence that reveals novel roles for wnt signaling in the injured CNS, and discuss possible mechanisms by which wnt ligands could overcome molecular barriers inhibiting axonal growth to promote regeneration. A central challenge in the neuroscience field is developing therapeutic strategies that induce robust axonal regeneration. Although adult axons have the capacity to respond to axonal guidance molecules after injury, there are several major obstacles for axonal growth, including extensive neuronal death, glial scars at the injury site, and lack of axonal guidance signals. Research in rodents demonstrated that activation of wnt/β-catenin signaling in retinal neurons and radial glia induced neuronal survival and axonal growth, but that activation within reactive glia at the injury site promoted proliferation and glial scar formation. Studies in zebrafish spinal cord injury models confirm an axonal regenerative role for wnt/β-catenin signaling and identified the cell types responsible. Additionally, in vitro and in vivo studies demonstrated that wnt induces axonal and neurite growth through transcription-dependent effects of its central mediator β-catenin, potentially by inducing regeneration-promoting genes. Canonical wnt signaling may also function through transcription-independent interactions of β-catenin with cytoskeletal elements, which could stabilize growing axons and control growth cone movement. Therefore, these studies suggest that wnt-induce

关键词： wnt signaling neuritogenesis retina retinal ganglion cell axonal growth regeneration spinal cord

A Comprehensive Overview of Skeletal Phenotypes Associated with Alterations in wnt/β-catenin signaling in Humans and Mice

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Bone Research 2013年第1期1卷 27-71页

作者： Kevin A.Maupin Casey J.Droscha Bart O.Williams Program for Skeletal Pathobiology and Center for Tumor Metastasis Van Andel Research Institute333 Bostwick NEGrand RapidsMI 49503USA

The wnt signaling pathway plays key roles in differentiation and development and alterations in this signaling pathway are causally associated with numerous human diseases. While several laboratories were examining roles for wnt signaling in skeletal development during the 1990s, interest in the pathway rose exponentially when three key papers were published in 2001-2002. One report found that loss of the wnt co-receptor, Low-density lipoprotein related protein-5 （LRPS）, was the underlying genetic cause of the syndrome Osteoporosis pseudoglioma （OPPG）. OPPG is characterized by early-onset osteoporosis causing increased susceptibility to debilitating fractures. Shortly thereafter, two groups reported that individuals carrying a specific point mutation in LRP5 （G171V） develop high-bone mass. Subsequent to this, the causative mechanisms for these observations heightened the need to understand the mechanisms by which wnt signaling controlled bone development and homeostasis and encouraged significant investment from biotechnology and pharmaceutical companies to develop methods to activate wnt signaling to increase bone mass to treat osteoporosis and other bone disease. In this review, we will briefly summarize the cellular mechanisms underlying wnt signaling and discuss the observations related to OPPG and the high-bone mass disorders that heightened the appreciation of the role of wnt signaling in normal bone development and homeostasis. We will then present a comprehensive overview of the core components of the pathway with an emphasis on the phenotypes associated with mice carrying genetically engineered mutations in these genes and clinical observations that further link alterations in the pathway to changes in human bone.

关键词： wnt signaling mouse models Lrp5/Lrp6 -catenin skeletal phenotypes

SFRP5 inhibits melanin synthesis of melanocytes in vitiligo by suppressing the wnt/b-catenin signaling

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Genes & Diseases 2021年第5期8卷 677-688页

作者： Daopei Zou Yangmei Chen Lingzhao Zhang Xiaohui Yuan Yujie Zhang Adelina Inggawati Pham Thi Kieu Nguyet Tianwen Gao Jin Chen Department of Dermatology The First Affiliated Hospital of Chongqing Medical UniversityChongqing400010PR China Key Laboratory of Clinical Laboratory Diagnostics Ministry of EducationChongqing Medical UniversityChongqing400016PR China Department of Dermatology Xijing HospitalFourth Military Medical UniversityXi’anShanxi Province710032PR China

Secreted frizzled-related protein 5(SFRP5)plays a pivotal role in regulating the development of many tissues and organs,however,as an inhibitor of wnt signaling,the role of SFRP5 in vitiligo remains unknown.Hence,we speculated that SFRP5 might be associated with melanogenesis in melanocytes by regulating wnt signaling in vitiligo.In this study,we found that SFRP5 was overexpressed in the skin lesions of patients with vitiligo.Compared with that in normal epidermal melanocytes(PIG1),the expression of SFRP5 was increased in vitiligo melanocytes(PIG3V).To investigate the effect of SFRP5 on melanin synthesis,PIG1 cells were infected with recombinant SFRP5 adenovirus(AdSFRP5),and PIG3V cells were infected with recombinant siSFRP5 adenovirus(AdsiSFRP5).The results showed that SFRP5 overexpression inhibited melanin synthesis in PIG1 cells through downregulation of microphthalmia-associated transcription factor(MITF)and its target proteins via suppression of the wnt/b-catenin signaling pathway.Accordingly,SFRP5 silencing increased melanin synthesis and activated the wnt signaling pathway in PIG3V cells.Moreover,SFRP5 overexpression also downregulated the transcriptional activity of T cell factor/lymphoid enhancer factor(TCF/LEF)in PIG1 cells.Furthermore,this inhibitory effect of SFRP5 on melanin synthesis was reversed by treatment with the b-catenin agonist,SKL2001.The inhibitory action of SFRP5 in pigmentation was further confirmed in vivo using a nude mouse model.Hence,our results indicate that SFRP5 can inhibit melanogenesis in melanocytes.Additionally,our findings showed that SFRP5 plays a vital role in the development of vitiligo,and thus may serve as a potential therapeutic target for vitiligo.

关键词： Melanin synthesis Melanocytes MITF SFRP5 Vitiligo wnt signaling