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Chaudhary JK, Danga AK, Kumari A, Bhardwaj A, Rath PC. Role of stem cells in ageing and age-related diseases. Mech Ageing Dev 2025; 225:112069. [PMID: 40324541 DOI: 10.1016/j.mad.2025.112069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 04/30/2025] [Accepted: 05/01/2025] [Indexed: 05/07/2025]
Abstract
Stem cell functions and ageing are deeply interconnected, continually influencing each other in multiple ways. Stem cells play a vital role in organ maintenance, regeneration, and homeostasis, all of which decline over time due to gradual reduction in their self-renewal, differentiation, and growth factor secretion potential. The functional decline is attributed to damaging extrinsic environmental factors and progressively worsening intrinsic genetic and biochemical processes. These ageing-associated deteriorative changes have been extensively documented, paving the way for the discovery of novel biomarkers of ageing for detection, diagnosis, and treatment of age-related diseases. Age-dependent changes in adult stem cells include numerical decline, loss of heterogeneity, and reduced self-renewal and differentiation, leading to a drastic reduction in regenerative potential and thereby driving the ageing process. Conversely, ageing also adversely alters the stem cell niche, disrupting the molecular pathways underlying stem cell homing, self-renewal, differentiation, and growth factor secretion, all of which are critical for tissue repair and regeneration. A holistic understanding of these molecular mechanisms, through empirical research and clinical trials, is essential for designing targeted therapies to modulate ageing and improve health parameters in older individuals.
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Affiliation(s)
- Jitendra Kumar Chaudhary
- Molecular Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India; Department of Zoology, Shivaji College, University of Delhi, New Delhi 110027, India.
| | - Ajay Kumar Danga
- Molecular Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India; National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
| | - Anita Kumari
- Molecular Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
| | - Akshay Bhardwaj
- Global Research Alliances, Ashoka University, Rajiv Gandhi Education City, Sonepat, Haryana 131029, India.
| | - Pramod C Rath
- Molecular Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
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2
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Zhang T, Liu J, Jin W, Nie H, Chen S, Tang X, Liu R, Wang M, Chen R, Lu J, Bao J, Jiang S, Xiao Y, Yan F. The sensory nerve regulates stem cell homeostasis through Wnt5a signaling. iScience 2024; 27:111035. [PMID: 39635121 PMCID: PMC11615182 DOI: 10.1016/j.isci.2024.111035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 06/13/2024] [Accepted: 09/23/2024] [Indexed: 12/07/2024] Open
Abstract
Increasing evidence indicates that nerves play a significant role in regulating stem cell homeostasis and developmental processes. To explore the impact of nerves on epithelial stem cell homeostasis during tooth development, the regulation of sensory nerves on stem cell homeostasis was investigated using a rat model of incisor development. Impaired mineralization, decreased enamel thickness, and fractured enamel rods of the incisor were observed after denervation. qPCR and histological staining revealed that the expression of enamel-related factors ameloblastin (AMBN), kallikrein-4, amelogenin (Amelx), collagen type XVII (col17a), and enamelin were decreased in the incisor enamel of rats with sensory nerve injure. The decreased expression of Wnt5a in ameloblasts was coupled with the downregulation of calcium ion-related calmodulin kinase II. These results implicate that the sensory nerves are essential in stem cell homeostasis for enamel mineralization and development.
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Affiliation(s)
- Ting Zhang
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China
| | - Jiaying Liu
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China
- School of Medicine and Dentistry, Griffith University, Gold Coast, QLD 4222, Australia
| | - Weiqiu Jin
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China
| | - Hua Nie
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China
| | - Sheng Chen
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China
| | - Xuna Tang
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China
| | - Rong Liu
- Department of Periodontology, Guiyang Hospital of Stomatology, Guiyang 550002, GuiZhou, China
| | - Min Wang
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China
| | - Rixin Chen
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China
| | - Jiangyue Lu
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China
| | - Jun Bao
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China
| | - Shaoyun Jiang
- Stomatological Center, Peking University Shenzhen Hospital, Guangdong Provincial High-level Clinical Key Specialty, Shenzhen Clinical Research Center for Oral Diseases, Guangdong Province Engineering Research Center of Oral Disease Diagnosis and Treatment, Shenzhen 5180036, Guangdong, China
| | - Yin Xiao
- School of Medicine and Dentistry, Griffith University, Gold Coast, QLD 4222, Australia
| | - Fuhua Yan
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China
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Guo T, Pei F, Zhang M, Yamada T, Feng J, Jing J, Ho TV, Chai Y. Vascular architecture regulates mesenchymal stromal cell heterogeneity via P53-PDGF signaling in the mouse incisor. Cell Stem Cell 2024; 31:904-920.e6. [PMID: 38703771 PMCID: PMC11162319 DOI: 10.1016/j.stem.2024.04.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 02/17/2024] [Accepted: 04/15/2024] [Indexed: 05/06/2024]
Abstract
Mesenchymal stem cells (MSCs) reside in niches to maintain tissue homeostasis and contribute to repair and regeneration. Although the physiological functions of blood and lymphatic vasculature are well studied, their regulation of MSCs as niche components remains largely unknown. Using adult mouse incisors as a model, we uncover the role of Trp53 in regulating vascular composition through THBS2 to maintain mesenchymal tissue homeostasis. Loss of Trp53 in GLI1+ progeny increases arteries and decreases other vessel types. Platelet-derived growth factors from arteries deposit in the MSC region and interact with PDGFRA and PDGFRB. Significantly, PDGFRA+ and PDGFRB+ cells differentially contribute to defined cell lineages in the adult mouse incisor. Collectively, our results highlight Trp53's importance in regulating the vascular niche for MSCs. They also shed light on how different arterial cells provide unique cues to regulate MSC subpopulations and maintain their heterogeneity. Furthermore, they provide mechanistic insight into MSC-vasculature crosstalk.
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Affiliation(s)
- Tingwei Guo
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA
| | - Fei Pei
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA
| | - Mingyi Zhang
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA
| | - Takahiko Yamada
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA
| | - Jifan Feng
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA
| | - Junjun Jing
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA
| | - Thach-Vu Ho
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA
| | - Yang Chai
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA.
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4
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Zhang M, Guo T, Pei F, Feng J, Jing J, Xu J, Yamada T, Ho TV, Du J, Sehgal P, Chai Y. ARID1B maintains mesenchymal stem cell quiescence via inhibition of BCL11B-mediated non-canonical Activin signaling. Nat Commun 2024; 15:4614. [PMID: 38816354 PMCID: PMC11139927 DOI: 10.1038/s41467-024-48285-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 04/24/2024] [Indexed: 06/01/2024] Open
Abstract
ARID1B haploinsufficiency in humans causes Coffin-Siris syndrome, associated with developmental delay, facial dysmorphism, and intellectual disability. The role of ARID1B has been widely studied in neuronal development, but whether it also regulates stem cells remains unknown. Here, we employ scRNA-seq and scATAC-seq to dissect the regulatory functions and mechanisms of ARID1B within mesenchymal stem cells (MSCs) using the mouse incisor model. We reveal that loss of Arid1b in the GLI1+ MSC lineage disturbs MSCs' quiescence and leads to their proliferation due to the ectopic activation of non-canonical Activin signaling via p-ERK. Furthermore, loss of Arid1b upregulates Bcl11b, which encodes a BAF complex subunit that modulates non-canonical Activin signaling by directly regulating the expression of activin A subunit, Inhba. Reduction of Bcl11b or non-canonical Activin signaling restores the MSC population in Arid1b mutant mice. Notably, we have identified that ARID1B suppresses Bcl11b expression via specific binding to its third intron, unveiling the direct inter-regulatory interactions among BAF subunits in MSCs. Our results demonstrate the vital role of ARID1B as an epigenetic modifier in maintaining MSC homeostasis and reveal its intricate mechanistic regulatory network in vivo, providing novel insights into the linkage between chromatin remodeling and stem cell fate determination.
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Affiliation(s)
- Mingyi Zhang
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Tingwei Guo
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Fei Pei
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Jifan Feng
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Junjun Jing
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Jian Xu
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Takahiko Yamada
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Thach-Vu Ho
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Jiahui Du
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Prerna Sehgal
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Yang Chai
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA.
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Hou XY, Danzeng LM, Wu YL, Ma QH, Yu Z, Li MY, Li LS. Mesenchymal stem cells and their derived exosomes for the treatment of COVID-19. World J Stem Cells 2024; 16:353-374. [PMID: 38690515 PMCID: PMC11056634 DOI: 10.4252/wjsc.v16.i4.353] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 02/17/2024] [Accepted: 03/15/2024] [Indexed: 04/25/2024] Open
Abstract
Coronavirus disease 2019 (COVID-19) is an acute respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection typically presents with fever and respiratory symptoms, which can progress to severe respiratory distress syndrome and multiple organ failure. In severe cases, these complications may even lead to death. One of the causes of COVID-19 deaths is the cytokine storm caused by an overactive immune response. Therefore, suppressing the overactive immune response may be an effective strategy for treating COVID-19. Mesenchymal stem cells (MSCs) and their derived exosomes (MSCs-Exo) have potent homing abilities, immunomodulatory functions, regenerative repair, and antifibrotic effects, promising an effective tool in treating COVID-19. In this paper, we review the main mechanisms and potential roles of MSCs and MSCs-Exo in treating COVID-19. We also summarize relevant recent clinical trials, including the source of cells, the dosage and the efficacy, and the clinical value and problems in this field, providing more theoretical references for the clinical use of MSCs and MSCs-Exo in the treatment of COVID-19.
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Affiliation(s)
- Xiang-Yi Hou
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, Jilin Province, China
| | - La-Mu Danzeng
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, Jilin Province, China
| | - Yi-Lin Wu
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, Jilin Province, China
| | - Qian-Hui Ma
- Department of Pharmacy, Jilin University, Changchun 130021, Jilin Province, China
| | - Zheng Yu
- The First Hospital of Jilin University, Jilin University, Changchun 130021, Jilin Province, China
| | - Mei-Ying Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, Jilin Province, China
| | - Li-Sha Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, Jilin Province, China.
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6
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Verma S, Lin X, Coulson-Thomas VJ. The Potential Reversible Transition between Stem Cells and Transient-Amplifying Cells: The Limbal Epithelial Stem Cell Perspective. Cells 2024; 13:748. [PMID: 38727284 PMCID: PMC11083486 DOI: 10.3390/cells13090748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 04/18/2024] [Accepted: 04/24/2024] [Indexed: 05/13/2024] Open
Abstract
Stem cells (SCs) undergo asymmetric division, producing transit-amplifying cells (TACs) with increased proliferative potential that move into tissues and ultimately differentiate into a specialized cell type. Thus, TACs represent an intermediary state between stem cells and differentiated cells. In the cornea, a population of stem cells resides in the limbal region, named the limbal epithelial stem cells (LESCs). As LESCs proliferate, they generate TACs that move centripetally into the cornea and differentiate into corneal epithelial cells. Upon limbal injury, research suggests a population of progenitor-like cells that exists within the cornea can move centrifugally into the limbus, where they dedifferentiate into LESCs. Herein, we summarize recent advances made in understanding the mechanism that governs the differentiation of LESCs into TACs, and thereafter, into corneal epithelial cells. We also outline the evidence in support of the existence of progenitor-like cells in the cornea and whether TACs could represent a population of cells with progenitor-like capabilities within the cornea. Furthermore, to gain further insights into the dynamics of TACs in the cornea, we outline the most recent findings in other organ systems that support the hypothesis that TACs can dedifferentiate into SCs.
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Affiliation(s)
- Sudhir Verma
- College of Optometry, University of Houston, 4901 Calhoun Road, Houston, TX 77204, USA;
- Deen Dayal Upadhyaya College, University of Delhi, Delhi 110078, India
| | - Xiao Lin
- College of Optometry, University of Houston, 4901 Calhoun Road, Houston, TX 77204, USA;
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Li F, Wang Z, Cao Y, Pei B, Luo X, Liu J, Ge P, Luo Y, Ma S, Chen H. Intestinal Mucosal Immune Barrier: A Powerful Firewall Against Severe Acute Pancreatitis-Associated Acute Lung Injury via the Gut-Lung Axis. J Inflamm Res 2024; 17:2173-2193. [PMID: 38617383 PMCID: PMC11016262 DOI: 10.2147/jir.s448819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 03/20/2024] [Indexed: 04/16/2024] Open
Abstract
The pathogenesis of severe acute pancreatitis-associated acute lung injury (SAP-ALI), which is the leading cause of mortality among hospitalized patients in the intensive care unit, remains incompletely elucidated. The intestinal mucosal immune barrier is a crucial component of the intestinal epithelial barrier, and its aberrant activation contributes to the induction of sustained pro-inflammatory immune responses, paradoxical intercellular communication, and bacterial translocation. In this review, we firstly provide a comprehensive overview of the composition of the intestinal mucosal immune barrier and its pivotal roles in the pathogenesis of SAP-ALI. Secondly, the mechanisms of its crosstalk with gut microbiota, which is called gut-lung axis, and its effect on SAP-ALI were summarized. Finally, a number of drugs that could enhance the intestinal mucosal immune barrier and exhibit potential anti-SAP-ALI activities were presented, including probiotics, glutamine, enteral nutrition, and traditional Chinese medicine (TCM). The aim is to offer a theoretical framework based on the perspective of the intestinal mucosal immune barrier to protect against SAP-ALI.
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Affiliation(s)
- Fan Li
- Department of General Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Laboratory of Integrative Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
| | - Zhengjian Wang
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People’s Republic of China
| | - Yinan Cao
- Department of General Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Laboratory of Integrative Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
| | - Boliang Pei
- Department of General Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Laboratory of Integrative Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
| | - Xinyu Luo
- Department of General Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Laboratory of Integrative Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
| | - Jin Liu
- Department of General Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Laboratory of Integrative Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
| | - Peng Ge
- Department of General Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Laboratory of Integrative Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
| | - Yalan Luo
- Department of General Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Laboratory of Integrative Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
| | - Shurong Ma
- Department of General Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Laboratory of Integrative Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
| | - Hailong Chen
- Department of General Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Laboratory of Integrative Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
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Xu X, Gong X, Zhang L, Zhang H, Sun Y. PRX1-positive mesenchymal stem cells drive molar morphogenesis. Int J Oral Sci 2024; 16:15. [PMID: 38369512 PMCID: PMC10874978 DOI: 10.1038/s41368-024-00277-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 12/29/2023] [Accepted: 12/30/2023] [Indexed: 02/20/2024] Open
Abstract
Mammalian teeth, developing inseparable from epithelial-mesenchymal interaction, come in many shapes and the key factors governing tooth morphology deserve to be answered. By merging single-cell RNA sequencing analysis with lineage tracing models, we have unearthed a captivating correlation between the contrasting morphology of mouse molars and the specific presence of PRX1+ cells within M1. These PRX1+ cells assume a profound responsibility in shaping tooth morphology through a remarkable divergence in dental mesenchymal cell proliferation. Deeper into the mechanisms, we have discovered that Wnt5a, bestowed by mesenchymal PRX1+ cells, stimulates mesenchymal cell proliferation while orchestrating molar morphogenesis through WNT signaling pathway. The loss of Wnt5a exhibits a defect phenotype similar to that of siPrx1. Exogenous addition of WNT5A can successfully reverse the inhibited cell proliferation and consequent deviant appearance exhibited in Prx1-deficient tooth germs. These findings bestow compelling evidence of PRX1-positive mesenchymal cells to be potential target in regulating tooth morphology.
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Affiliation(s)
- Xiaoqiao Xu
- Department of Implantology, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Xuyan Gong
- Department of Implantology, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Lei Zhang
- Department of Implantology, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Han Zhang
- Department of Implantology, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Yao Sun
- Department of Implantology, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China.
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9
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Sarabia-Sánchez MA, Robles-Flores M. WNT Signaling in Stem Cells: A Look into the Non-Canonical Pathway. Stem Cell Rev Rep 2024; 20:52-66. [PMID: 37804416 PMCID: PMC10799802 DOI: 10.1007/s12015-023-10610-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/17/2023] [Indexed: 10/09/2023]
Abstract
Tissue homeostasis is crucial for multicellular organisms, wherein the loss of cells is compensated by generating new cells with the capacity for proliferation and differentiation. At the origin of these populations are the stem cells, which have the potential to give rise to cells with both capabilities, and persevere for a long time through the self-renewal and quiescence. Since the discovery of stem cells, an enormous effort has been focused on learning about their functions and the molecular regulation behind them. Wnt signaling is widely recognized as essential for normal and cancer stem cell. Moreover, β-catenin-dependent Wnt pathway, referred to as canonical, has gained attention, while β-catenin-independent Wnt pathways, known as non-canonical, have remained conspicuously less explored. However, recent evidence about non-canonical Wnt pathways in stem cells begins to lay the foundations of a conceivably vast field, and on which we aim to explain this in the present review. In this regard, we addressed the different aspects in which non-canonical Wnt pathways impact the properties of stem cells, both under normal conditions and also under disease, specifically in cancer.
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Affiliation(s)
- Miguel Angel Sarabia-Sánchez
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Martha Robles-Flores
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico.
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10
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Sui BD, Zheng CX, Zhao WM, Xuan K, Li B, Jin Y. Mesenchymal condensation in tooth development and regeneration: a focus on translational aspects of organogenesis. Physiol Rev 2023; 103:1899-1964. [PMID: 36656056 DOI: 10.1152/physrev.00019.2022] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 12/26/2022] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
The teeth are vertebrate-specific, highly specialized organs performing fundamental functions of mastication and speech, the maintenance of which is crucial for orofacial homeostasis and is further linked to systemic health and human psychosocial well-being. However, with limited ability for self-repair, the teeth can often be impaired by traumatic, inflammatory, and progressive insults, leading to high prevalence of tooth loss and defects worldwide. Regenerative medicine holds the promise to achieve physiological restoration of lost or damaged organs, and in particular an evolving framework of developmental engineering has pioneered functional tooth regeneration by harnessing the odontogenic program. As a key event of tooth morphogenesis, mesenchymal condensation dictates dental tissue formation and patterning through cellular self-organization and signaling interaction with the epithelium, which provides a representative to decipher organogenetic mechanisms and can be leveraged for regenerative purposes. In this review, we summarize how mesenchymal condensation spatiotemporally assembles from dental stem cells (DSCs) and sequentially mediates tooth development. We highlight condensation-mimetic engineering efforts and mechanisms based on ex vivo aggregation of DSCs, which have achieved functionally robust and physiologically relevant tooth regeneration after implantation in animals and in humans. The discussion of this aspect will add to the knowledge of development-inspired tissue engineering strategies and will offer benefits to propel clinical organ regeneration.
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Affiliation(s)
- Bing-Dong Sui
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Chen-Xi Zheng
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Wan-Min Zhao
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Kun Xuan
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China
- Department of Preventive Dentistry, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Bei Li
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yan Jin
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China
- Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi, China
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11
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Cancedda R, Mastrogiacomo M. Transit Amplifying Cells (TACs): a still not fully understood cell population. Front Bioeng Biotechnol 2023; 11:1189225. [PMID: 37229487 PMCID: PMC10203484 DOI: 10.3389/fbioe.2023.1189225] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Accepted: 04/27/2023] [Indexed: 05/27/2023] Open
Abstract
Maintenance of tissue homeostasis and tissue regeneration after an insult are essential functions of adult stem cells (SCs). In adult tissues, SCs proliferate at a very slow rate within "stem cell niches", but, during tissue development and regeneration, before giving rise to differentiated cells, they give rise to multipotent and highly proliferative cells, known as transit-amplifying cells (TACs). Although differences exist in diverse tissues, TACs are not only a transitory phase from SCs to post-mitotic cells, but they also actively control proliferation and number of their ancestor SCs and proliferation and differentiation of their progeny toward tissue specific functional cells. Autocrine signals and negative and positive feedback and feedforward paracrine signals play a major role in these controls. In the present review we will consider the generation and the role played by TACs during development and regeneration of lining epithelia characterized by a high turnover including epidermis and hair follicles, ocular epithelial surfaces, and intestinal mucosa. A comparison between these different tissues will be made. There are some genes and molecular pathways whose expression and activation are common to most TACs regardless their tissue of origin. These include, among others, Wnt, Notch, Hedgehog and BMP pathways. However, the response to these molecular signals can vary in TACs of different tissues. Secondly, we will consider cultured cells derived from tissues of mesodermal origin and widely adopted for cell therapy treatments. These include mesenchymal stem cells and dedifferentiated chondrocytes. The possible correlation between cell dedifferentiation and reversion to a transit amplifying cell stage will be discussed.
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Affiliation(s)
- Ranieri Cancedda
- Emeritus Professor, Università degli Studi di Genova, Genoa, Italy
| | - Maddalena Mastrogiacomo
- Dipartimento di Medicina Interna e Specialità Mediche (DIMI), Università Degli Studi di Genova, Genova, Italy
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12
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Li P, Ou Q, Shi S, Shao C. Immunomodulatory properties of mesenchymal stem cells/dental stem cells and their therapeutic applications. Cell Mol Immunol 2023; 20:558-569. [PMID: 36973490 PMCID: PMC10040934 DOI: 10.1038/s41423-023-00998-y] [Citation(s) in RCA: 74] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Accepted: 03/02/2023] [Indexed: 03/29/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are widely distributed in the body and play essential roles in tissue regeneration and homeostasis. MSCs can be isolated from discarded tissues, expanded in vitro and used as therapeutics for autoimmune diseases and other chronic disorders. MSCs promote tissue regeneration and homeostasis by primarily acting on immune cells. At least six different types of MSCs have been isolated from postnatal dental tissues and have remarkable immunomodulatory properties. Dental stem cells (DSCs) have been demonstrated to have therapeutic effects on several systemic inflammatory diseases. Conversely, MSCs derived from nondental tissues such as the umbilical cord exhibit great benefits in the management of periodontitis in preclinical studies. Here, we discuss the main therapeutic uses of MSCs/DSCs, their mechanisms, extrinsic inflammatory cues and the intrinsic metabolic circuitries that govern the immunomodulatory functions of MSCs/DSCs. Increased understanding of the mechanisms underpinning the immunomodulatory functions of MSCs/DSCs is expected to aid in the development of more potent and precise MSC/DSC-based therapeutics.
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Affiliation(s)
- Peishan Li
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, PR China
| | - Qianmin Ou
- South China Center of Craniofacial Stem Cell Research, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, PR China
| | - Songtao Shi
- South China Center of Craniofacial Stem Cell Research, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, PR China.
| | - Changshun Shao
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, PR China.
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13
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Pei F, Ma L, Jing J, Feng J, Yuan Y, Guo T, Han X, Ho TV, Lei J, He J, Zhang M, Chen JF, Chai Y. Sensory nerve niche regulates mesenchymal stem cell homeostasis via FGF/mTOR/autophagy axis. Nat Commun 2023; 14:344. [PMID: 36670126 PMCID: PMC9859800 DOI: 10.1038/s41467-023-35977-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 01/10/2023] [Indexed: 01/22/2023] Open
Abstract
Mesenchymal stem cells (MSCs) reside in microenvironments, referred to as niches, which provide structural support and molecular signals. Sensory nerves are niche components in the homeostasis of tissues such as skin, bone marrow and hematopoietic system. However, how the sensory nerve affects the behavior of MSCs remains largely unknown. Here we show that the sensory nerve is vital for mesenchymal tissue homeostasis and maintenance of MSCs in the continuously growing adult mouse incisor. Loss of sensory innervation leads to mesenchymal disorder and a decrease in MSCs. Mechanistically, FGF1 from the sensory nerve directly acts on MSCs by binding to FGFR1 and activates the mTOR/autophagy axis to sustain MSCs. Modulation of mTOR/autophagy restores the MSCs and rescues the mesenchymal tissue disorder of Fgfr1 mutant mice. Collectively, our study provides insights into the role of sensory nerves in the regulation of MSC homeostasis and the mechanism governing it.
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Affiliation(s)
- Fei Pei
- Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA, 90033, USA
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, 430079, Wuhan, China
| | - Li Ma
- Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA, 90033, USA
| | - Junjun Jing
- Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA, 90033, USA
| | - Jifan Feng
- Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA, 90033, USA
| | - Yuan Yuan
- Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA, 90033, USA
| | - Tingwei Guo
- Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA, 90033, USA
| | - Xia Han
- Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA, 90033, USA
| | - Thach-Vu Ho
- Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA, 90033, USA
| | - Jie Lei
- Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA, 90033, USA
| | - Jinzhi He
- Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA, 90033, USA
| | - Mingyi Zhang
- Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA, 90033, USA
| | - Jian-Fu Chen
- Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA, 90033, USA
| | - Yang Chai
- Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA, 90033, USA.
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14
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Jing J, Zhang M, Guo T, Pei F, Yang Y, Chai Y. Rodent incisor as a model to study mesenchymal stem cells in tissue homeostasis and repair. FRONTIERS IN DENTAL MEDICINE 2022. [DOI: 10.3389/fdmed.2022.1068494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
Abstract
The homeostasis of adult tissues, such as skin, hair, blood, and bone, requires continuous generation of differentiated progeny of stem cells. The rodent incisor undergoes constant renewal and can provide an extraordinary model for studying stem cells and their progeny in adult tissue homeostasis, cell differentiation and injury-induced regeneration. Meanwhile, cellular heterogeneity in the mouse incisor also provides an opportunity to study cell-cell communication between different cell types, including interactions between stem cells and their niche environment. More importantly, the molecular and cellular regulatory mechanisms revealed by the mouse incisor have broad implications for other organs. Here we review recent findings and advances using the mouse incisor as a model, including perspectives on the heterogeneity of cells in the mesenchyme, the niche environment, and signaling networks that regulate stem cell behavior. The progress from this field will not only expand the knowledge of stem cells and organogenesis, but also bridge a gap between animal models and tissue regeneration.
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15
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Xin Y, Lyu P, Jiang J, Zhou F, Wang J, Blackshaw S, Qian J. LRLoop: a method to predict feedback loops in cell-cell communication. Bioinformatics 2022; 38:4117-4126. [PMID: 35788263 PMCID: PMC9438954 DOI: 10.1093/bioinformatics/btac447] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 06/24/2022] [Accepted: 07/03/2022] [Indexed: 12/24/2022] Open
Abstract
MOTIVATION Intercellular communication (i.e. cell-cell communication) plays an essential role in multicellular organisms coordinating various biological processes. Previous studies discovered that feedback loops between two cell types are a widespread and vital signaling motif regulating development, regeneration and cancer progression. While many computational methods have been developed to predict cell-cell communication based on gene expression datasets, these methods often predict one-directional ligand-receptor interactions from sender to receiver cells and are not suitable to identify feedback loops. RESULTS Here, we describe ligand-receptor loop (LRLoop), a new method for analyzing cell-cell communication based on bi-directional ligand-receptor interactions, where two pairs of ligand-receptor interactions are identified that are responsive to each other and thereby form a closed feedback loop. We first assessed LRLoop using bulk datasets and found our method significantly reduces the false positive rate seen with existing methods. Furthermore, we developed a new strategy to assess the performance of these methods in single-cell datasets. We used the between-tissue interactions as an indicator of potential false-positive prediction and found that LRLoop produced a lower fraction of between-tissue interactions than traditional methods. Finally, we applied LRLoop to the single-cell datasets obtained from retinal development. We discovered many new bi-directional ligand-receptor interactions among individual cell types that potentially control proliferation, neurogenesis and/or cell fate specification. AVAILABILITY AND IMPLEMENTATION An R package is available at https://github.com/Pinlyu3/LRLoop. The source code can be found at figshare (https://doi.org/10.6084/m9.figshare.20126138.v1). The datasets can be found at figshare (https://doi.org/10.6084/m9.figshare.20126021.v1). SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Ying Xin
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Pin Lyu
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Junyao Jiang
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Fengquan Zhou
- Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Jie Wang
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Seth Blackshaw
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Jiang Qian
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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16
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Exploring the Immunomodulatory Aspect of Mesenchymal Stem Cells for Treatment of Severe Coronavirus Disease 19. Cells 2022; 11:cells11142175. [PMID: 35883618 PMCID: PMC9322532 DOI: 10.3390/cells11142175] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/24/2022] [Accepted: 06/25/2022] [Indexed: 02/06/2023] Open
Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is an enveloped, positive sense, single stranded RNA (+ssRNA) virus, belonging to the genus Betacoronavirus and family Coronaviridae. It is primarily transmitted from infected persons to healthy ones through inhalation of virus-laden respiratory droplets. After an average incubation period of 2–14 days, the majority of infected individuals remain asymptomatic and/or mildly symptomatic, whereas the remaining individuals manifest a myriad of clinical symptoms, including fever, sore throat, dry cough, fatigue, chest pain, and breathlessness. SARS-CoV-2 exploits the angiotensin converting enzyme 2 (ACE-2) receptor for cellular invasion, and lungs are amongst the most adversely affected organs in the body. Thereupon, immune responses are elicited, which may devolve into a cytokine storm characterized by enhanced secretion of multitude of inflammatory cytokines/chemokines and growth factors, such as interleukin (IL)-2, IL-6, IL-7, IL-8, IL-9, tumor necrosis factor alpha (TNF-α), granulocyte colony-stimulating factor (GCSF), basic fibroblast growth factor 2 (bFGF2), monocyte chemotactic protein-1 (MCP1), interferon-inducible protein 10 (IP10), macrophage inflammatory protein 1A (MIP1A), platelet-derived growth factor subunit B (PDGFB), and vascular endothelial factor (VEGF)-A. The systemic persistence of inflammatory molecules causes widespread histological injury, leading to functional deterioration of the infected organ(s). Although multiple treatment modalities with varying effectiveness are being employed, nevertheless, there is no curative COVID-19 therapy available to date. In this regard, one plausible supportive therapeutic modality may involve administration of mesenchymal stem cells (MSCs) and/or MSC-derived bioactive factors-based secretome to critically ill COVID-19 patients with the intention of accomplishing better clinical outcome owing to their empirically established beneficial effects. MSCs are well established adult stem cells (ASCs) with respect to their immunomodulatory, anti-inflammatory, anti-oxidative, anti-apoptotic, pro-angiogenic, and pro-regenerative properties. The immunomodulatory capabilities of MSCs are not constitutive but rather are highly dependent on a holistic niche. Following intravenous infusion, MSCs are known to undergo considerable histological trapping in the lungs and, therefore, become well positioned to directly engage with lung infiltrating immune cells, and thereby mitigate excessive inflammation and reverse/regenerate damaged alveolar epithelial cells and associated tissue post SARS-CoV-2 infection. Considering the myriad of abovementioned biologically beneficial properties and emerging translational insights, MSCs may be used as potential supportive therapy to counteract cytokine storms and reduce disease severity, thereby facilitating speedy recovery and health restoration.
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17
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Pincha N, Marangoni P, Haque A, Klein OD. Parallels in signaling between development and regeneration in ectodermal organs. Curr Top Dev Biol 2022; 149:373-419. [PMID: 35606061 PMCID: PMC10049776 DOI: 10.1016/bs.ctdb.2022.02.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Ectodermal organs originate from the outermost germ layer of the developing embryo and include the skin, hair, tooth, nails, and exocrine glands. These organs develop through tightly regulated, sequential and reciprocal epithelial-mesenchymal crosstalk, and they eventually assume various morphologies and functions while retaining the ability to regenerate. As with many other tissues in the body, the development and morphogenesis of these organs are regulated by a set of common signaling pathways, such as Shh, Wnt, Bmp, Notch, Tgf-β, and Eda. However, subtle differences in the temporal activation, the multiple possible combinations of ligand-receptor activation, the various cofactors, as well as the underlying epigenetic modulation determine how each organ develops into its adult form. Although each organ has been studied separately in considerable detail, the mechanisms underlying the parallels and differences in signaling that regulate their development have rarely been investigated. First, we will use the tooth, the hair follicle, and the mammary gland as representative ectodermal organs to explore how the development of signaling centers and establishment of stem cell populations influence overall growth and morphogenesis. Then we will compare how some of the major signaling pathways (Shh, Wnt, Notch and Yap/Taz) differentially regulate developmental events. Finally, we will discuss how signaling regulates regenerative processes in all three.
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Affiliation(s)
- Neha Pincha
- Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, CA, United States
| | - Pauline Marangoni
- Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, CA, United States
| | - Ameera Haque
- Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, CA, United States
| | - Ophir D Klein
- Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, CA, United States; Department of Pediatrics and Institute for Human Genetics, University of California, San Francisco, CA, United States.
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18
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Hermans F, Hemeryck L, Lambrichts I, Bronckaers A, Vankelecom H. Intertwined Signaling Pathways Governing Tooth Development: A Give-and-Take Between Canonical Wnt and Shh. Front Cell Dev Biol 2021; 9:758203. [PMID: 34778267 PMCID: PMC8586510 DOI: 10.3389/fcell.2021.758203] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 10/11/2021] [Indexed: 11/13/2022] Open
Abstract
Teeth play essential roles in life. Their development relies on reciprocal interactions between the ectoderm-derived dental epithelium and the underlying neural crest-originated mesenchyme. This odontogenic process serves as a prototype model for the development of ectodermal appendages. In the mouse, developing teeth go through distinct morphological phases that are tightly controlled by epithelial signaling centers. Crucial molecular regulators of odontogenesis include the evolutionarily conserved Wnt, BMP, FGF and sonic hedgehog (Shh) pathways. These signaling modules do not act on their own, but are closely intertwined during tooth development, thereby outlining the path to be taken by specific cell populations including the resident dental stem cells. Recently, pivotal Wnt-Shh interaction and feedback loops have been uncovered during odontogenesis, showing conservation in other developing ectodermal appendages. This review provides an integrated overview of the interplay between canonical Wnt and Shh throughout mouse tooth formation stages, extending from the initiation of dental placode to the fully formed adult tooth.
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Affiliation(s)
- Florian Hermans
- Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, Department of Development and Regeneration, Leuven Stem Cell Institute, KU Leuven (University of Leuven), Leuven, Belgium.,Biomedical Research Institute (BIOMED), Department of Cardio and Organ Systems, UHasselt-Hasselt University, Diepenbeek, Belgium
| | - Lara Hemeryck
- Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, Department of Development and Regeneration, Leuven Stem Cell Institute, KU Leuven (University of Leuven), Leuven, Belgium
| | - Ivo Lambrichts
- Biomedical Research Institute (BIOMED), Department of Cardio and Organ Systems, UHasselt-Hasselt University, Diepenbeek, Belgium
| | - Annelies Bronckaers
- Biomedical Research Institute (BIOMED), Department of Cardio and Organ Systems, UHasselt-Hasselt University, Diepenbeek, Belgium
| | - Hugo Vankelecom
- Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, Department of Development and Regeneration, Leuven Stem Cell Institute, KU Leuven (University of Leuven), Leuven, Belgium
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19
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Du J, Jing J, Chen S, Yuan Y, Feng J, Ho TV, Sehgal P, Xu J, Jiang X, Chai Y. Arid1a regulates cell cycle exit of transit-amplifying cells by inhibiting the Aurka-Cdk1 axis in mouse incisor. Development 2021; 148:dev198838. [PMID: 33766930 PMCID: PMC8077510 DOI: 10.1242/dev.198838] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 03/18/2021] [Indexed: 12/14/2022]
Abstract
Stem cells self-renew or give rise to transit-amplifying cells (TACs) that differentiate into specific functional cell types. The fate determination of stem cells to TACs and their transition to fully differentiated progeny is precisely regulated to maintain tissue homeostasis. Arid1a, a core component of the switch/sucrose nonfermentable complex, performs epigenetic regulation of stage- and tissue-specific genes that is indispensable for stem cell homeostasis and differentiation. However, the functional mechanism of Arid1a in the fate commitment of mesenchymal stem cells (MSCs) and their progeny is not clear. Using the continuously growing adult mouse incisor model, we show that Arid1a maintains tissue homeostasis through limiting proliferation, promoting cell cycle exit and differentiation of TACs by inhibiting the Aurka-Cdk1 axis. Loss of Arid1a overactivates the Aurka-Cdk1 axis, leading to expansion of the mitotic TAC population but compromising their differentiation ability. Furthermore, the defective homeostasis after loss of Arid1a ultimately leads to reduction of the MSC population. These findings reveal the functional significance of Arid1a in regulating the fate of TACs and their interaction with MSCs to maintain tissue homeostasis.
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Affiliation(s)
- Jiahui Du
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Junjun Jing
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Shuo Chen
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Yuan Yuan
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Jifan Feng
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Thach-Vu Ho
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Prerna Sehgal
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Jian Xu
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Xinquan Jiang
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Yang Chai
- Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, 90033, USA
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