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Physiological Reviews Jul 2022Salivary glands produce and secrete saliva, which is essential for maintaining oral health and overall health. Understanding both the unique structure and physiological... (Review)
Review
Salivary glands produce and secrete saliva, which is essential for maintaining oral health and overall health. Understanding both the unique structure and physiological function of salivary glands, as well as how they are affected by disease and injury, will direct the development of therapy to repair and regenerate them. Significant recent advances, particularly in the OMICS field, increase our understanding of how salivary glands develop at the cellular, molecular, and genetic levels: the signaling pathways involved, the dynamics of progenitor cell lineages in development, homeostasis, and regeneration, and the role of the extracellular matrix microenvironment. These provide a template for cell and gene therapies as well as bioengineering approaches to repair or regenerate salivary function.
Topics: Cell Lineage; Humans; Oral Health; Regeneration; Salivary Glands; Signal Transduction
PubMed: 35343828
DOI: 10.1152/physrev.00015.2021 -
Physiological Reviews Oct 2015After decades of believing the heart loses the ability to regenerate soon after birth, numerous studies are now reporting that the adult heart may indeed be capable of... (Review)
Review
After decades of believing the heart loses the ability to regenerate soon after birth, numerous studies are now reporting that the adult heart may indeed be capable of regeneration, although the magnitude of new cardiac myocyte formation varies greatly. While this debate has energized the field of cardiac regeneration and led to a dramatic increase in our understanding of cardiac growth and repair, it has left much confusion in the field as to the prospects of regenerating the heart. Studies applying modern techniques of genetic lineage tracing and carbon-14 dating have begun to establish limits on the amount of endogenous regeneration after cardiac injury, but the underlying cellular mechanisms of this regeneration remained unclear. These same studies have also revealed an astonishing capacity for cardiac repair early in life that is largely lost with adult differentiation and maturation. Regardless, this renewed focus on cardiac regeneration as a therapeutic goal holds great promise as a novel strategy to address the leading cause of death in the developed world.
Topics: Animals; Cell Differentiation; Heart; Heart Diseases; Humans; Myocytes, Cardiac; Regeneration; Stem Cells
PubMed: 26269526
DOI: 10.1152/physrev.00021.2014 -
The Journal of the American Academy of... May 2013Cartilage damaged by trauma has a limited capacity to regenerate. Current methods of managing small chondral defects include palliative treatment with arthroscopic... (Review)
Review
Cartilage damaged by trauma has a limited capacity to regenerate. Current methods of managing small chondral defects include palliative treatment with arthroscopic débridement and lavage, reparative treatment with marrow-stimulation techniques (eg, microfracture), and restorative treatment, including osteochondral grafting and autologous chondrocyte implantation. Larger defects are managed with osteochondral allograft or total joint arthroplasty. However, the future of managing cartilage defects lies in providing biologic solutions through cartilage regeneration. Laboratory and clinical studies have examined the management of larger lesions using tissue-engineered cartilage. Regenerated cartilage can be derived from various cell types, including chondrocytes, pluripotent stem cells, and mesenchymal stem cells. Common scaffolding materials include proteins, carbohydrates, synthetic materials, and composite polymers. Scaffolds may be woven, spun into nanofibers, or configured as hydrogels. Chondrogenesis may be enhanced with the application of chondroinductive growth factors. Bioreactors are being developed to enhance nutrient delivery and provide mechanical stimulation to tissue-engineered cartilage ex vivo. The multidisciplinary approaches currently being developed to produce cartilage promise to bring to fruition the desire for cartilage regeneration in clinical use.
Topics: Animals; Bioreactors; Cartilage, Articular; Cell Differentiation; Chondrocytes; Fibroblast Growth Factors; Humans; Mesenchymal Stem Cells; Platelet-Rich Plasma; Prosthesis Design; Regeneration; Tissue Engineering; Tissue Scaffolds; Transforming Growth Factor beta; Transplantation, Autologous
PubMed: 23637149
DOI: 10.5435/JAAOS-21-05-303 -
Nature Mar 2010Although mammalian hearts show almost no ability to regenerate, there is a growing initiative to determine whether existing cardiomyocytes or progenitor cells can be...
Although mammalian hearts show almost no ability to regenerate, there is a growing initiative to determine whether existing cardiomyocytes or progenitor cells can be coaxed into eliciting a regenerative response. In contrast to mammals, several non-mammalian vertebrate species are able to regenerate their hearts, including the zebrafish, which can fully regenerate its heart after amputation of up to 20% of the ventricle. To address directly the source of newly formed cardiomyocytes during zebrafish heart regeneration, we first established a genetic strategy to trace the lineage of cardiomyocytes in the adult fish, on the basis of the Cre/lox system widely used in the mouse. Here we use this system to show that regenerated heart muscle cells are derived from the proliferation of differentiated cardiomyocytes. Furthermore, we show that proliferating cardiomyocytes undergo limited dedifferentiation characterized by the disassembly of their sarcomeric structure, detachment from one another and the expression of regulators of cell-cycle progression. Specifically, we show that the gene product of polo-like kinase 1 (plk1) is an essential component of cardiomyocyte proliferation during heart regeneration. Our data provide the first direct evidence for the source of proliferating cardiomyocytes during zebrafish heart regeneration and indicate that stem or progenitor cells are not significantly involved in this process.
Topics: Animals; Cell Cycle Proteins; Cell Dedifferentiation; Cell Lineage; Cell Proliferation; Gene Expression Regulation; Heart; Myocytes, Cardiac; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Regeneration; Sarcomeres; Zebrafish; Polo-Like Kinase 1
PubMed: 20336145
DOI: 10.1038/nature08899 -
Proceedings of the National Academy of... Mar 2020Aging manifests with architectural alteration and functional decline of multiple organs throughout an organism. In mammals, aged skin is accompanied by a marked...
Aging manifests with architectural alteration and functional decline of multiple organs throughout an organism. In mammals, aged skin is accompanied by a marked reduction in hair cycling and appearance of bald patches, leading researchers to propose that hair follicle stem cells (HFSCs) are either lost, differentiate, or change to an epidermal fate during aging. Here, we employed single-cell RNA-sequencing to interrogate aging-related changes in the HFSCs. Surprisingly, although numbers declined, aging HFSCs were present, maintained their identity, and showed no overt signs of shifting to an epidermal fate. However, they did exhibit prevalent transcriptional changes particularly in extracellular matrix genes, and this was accompanied by profound structural perturbations in the aging SC niche. Moreover, marked age-related changes occurred in many nonepithelial cell types, including resident immune cells, sensory neurons, and arrector pili muscles. Each of these SC niche components has been shown to influence HF regeneration. When we performed skin injuries that are known to mobilize young HFSCs to exit their niche and regenerate HFs, we discovered that aged skin is defective at doing so. Interestingly, however, in transplantation assays in vivo, aged HFSCs regenerated HFs when supported with young dermis, while young HFSCs failed to regenerate HFs when combined with aged dermis. Together, our findings highlight the importance of SC:niche interactions and favor a model where youthfulness of the niche microenvironment plays a dominant role in dictating the properties of its SCs and tissue health and fitness.
Topics: Animals; Dermis; Epidermal Cells; Epidermis; Hair Follicle; Mice; Mice, Inbred C57BL; Muscles; Re-Epithelialization; Regeneration; Sensory Receptor Cells; Skin Aging; Stem Cell Niche; Stem Cell Transplantation; Stem Cells; Transcriptome; Wound Healing
PubMed: 32094197
DOI: 10.1073/pnas.1901720117 -
Developmental Cell Apr 2020The adult mammalian heart is incapable of regeneration following injury. In contrast, the neonatal mouse heart can efficiently regenerate during the first week of life....
The adult mammalian heart is incapable of regeneration following injury. In contrast, the neonatal mouse heart can efficiently regenerate during the first week of life. The molecular mechanisms that mediate the regenerative response and its blockade in later life are not understood. Here, by single-nucleus RNA sequencing, we map the dynamic transcriptional landscape of five distinct cardiomyocyte populations in healthy, injured, and regenerating mouse hearts. We identify immature cardiomyocytes that enter the cell cycle following injury and disappear as the heart loses the ability to regenerate. These proliferative neonatal cardiomyocytes display a unique transcriptional program dependent on nuclear transcription factor Y subunit alpha (NFYa) and nuclear factor erythroid 2-like 1 (NFE2L1) transcription factors, which exert proliferative and protective functions, respectively. Cardiac overexpression of these two factors conferred protection against ischemic injury in mature mouse hearts that were otherwise non-regenerative. These findings advance our understanding of the cellular basis of neonatal heart regeneration and reveal a transcriptional landscape for heart repair following injury.
Topics: Animals; Animals, Newborn; Cell Cycle; Cell Proliferation; Gene Expression Regulation, Developmental; Heart; Myocardial Infarction; Myocytes, Cardiac; Regeneration; Transcription Factors
PubMed: 32220304
DOI: 10.1016/j.devcel.2020.02.019 -
JCI Insight Nov 2020Adult liver has enormous regenerative capacity; it can regenerate after losing two-thirds of its mass while sustaining essential metabolic functions. How the liver...
Adult liver has enormous regenerative capacity; it can regenerate after losing two-thirds of its mass while sustaining essential metabolic functions. How the liver balances dual demands for increased proliferative activity with maintenance of organ function is unknown but essential to prevent liver failure. Using partial hepatectomy (PHx) in mice to model liver regeneration, we integrated single-cell RNA- and ATAC-Seq to map state transitions in approximately 13,000 hepatocytes at single-cell resolution as livers regenerated, and validated key findings with IHC, to uncover how the organ regenerates hepatocytes while simultaneously fulfilling its vital tissue-specific functions. After PHx, hepatocytes rapidly and transiently diversified into multiple distinct populations with distinct functional bifurcation: some retained the chromatin landscapes and transcriptomes of hepatocytes in undamaged adult livers, whereas others transitioned to acquire chromatin landscapes and transcriptomes of fetal hepatocytes. Injury-related signaling pathways known to be critical for regeneration were activated in transitioning hepatocytes, and the most fetal-like hepatocytes exhibited chromatin landscapes that were enriched with transcription factors regulated by those pathways.
Topics: Animals; Biomarkers; Cell Proliferation; Hepatocytes; Liver; Liver Regeneration; Male; Mice; Mice, Inbred C57BL; Signal Transduction; Single-Cell Analysis
PubMed: 33208554
DOI: 10.1172/jci.insight.141024 -
Development (Cambridge, England) Mar 2013Planarians are flatworms capable of regenerating all body parts. Planarian regeneration requires neoblasts, a population of dividing cells that has been studied for over... (Review)
Review
Planarians are flatworms capable of regenerating all body parts. Planarian regeneration requires neoblasts, a population of dividing cells that has been studied for over a century. Neoblast progeny generate new cells of blastemas, which are the regenerative outgrowths at wounds. If the neoblasts comprise a uniform population of cells during regeneration (e.g. they are all uncommitted and pluripotent), then specialization of new cell types should occur in multipotent, non-dividing neoblast progeny cells. By contrast, recent data indicate that some neoblasts express lineage-specific transcription factors during regeneration and in uninjured animals. These observations raise the possibility that an important early step in planarian regeneration is the specialization of neoblasts to produce specified rather than naïve blastema cells.
Topics: Animals; Cell Differentiation; Humans; Models, Biological; Organ Specificity; Planarians; Regeneration; Stem Cells; Wound Healing
PubMed: 23404104
DOI: 10.1242/dev.080499 -
Nature Reviews. Genetics Sep 2020Regeneration is the process by which organisms replace lost or damaged tissue, and regenerative capacity can vary greatly among species, tissues and life stages. Tissue... (Review)
Review
Regeneration is the process by which organisms replace lost or damaged tissue, and regenerative capacity can vary greatly among species, tissues and life stages. Tissue regeneration shares certain hallmarks of embryonic development, in that lineage-specific factors can be repurposed upon injury to initiate morphogenesis; however, many differences exist between regeneration and embryogenesis. Recent studies of regenerating tissues in laboratory model organisms - such as acoel worms, frogs, fish and mice - have revealed that chromatin structure, dedicated enhancers and transcriptional networks are regulated in a context-specific manner to control key gene expression programmes. A deeper mechanistic understanding of the gene regulatory networks of regeneration pathways might ultimately enable their targeted reactivation as a means to treat human injuries and degenerative diseases. In this Review, we consider the regeneration of body parts across a range of tissues and species to explore common themes and potentially exploitable elements.
Topics: Animals; Gene Regulatory Networks; Humans; Regeneration
PubMed: 32504079
DOI: 10.1038/s41576-020-0239-7 -
Developmental Biology Apr 2019Regenerative ability is highly variable among the metazoans. While many invertebrate organisms are capable of complete regeneration of entire bodies and organs,... (Review)
Review
Regenerative ability is highly variable among the metazoans. While many invertebrate organisms are capable of complete regeneration of entire bodies and organs, whole-organ regeneration is limited to very few species in the vertebrate lineages. Tunicates, which are invertebrate chordates and the closest extant relatives of the vertebrates, show robust regenerative ability. Colonial ascidians of the family of the Styelidae, such as several species of Botrylloides, are able to regenerate entire new bodies from nothing but fragments of vasculature, and they are the only chordates that are capable of whole body regeneration. The cell types and signaling pathways involved in whole body regeneration are not well understood, but some evidence suggests that blood borne cells may play a role. Solitary ascidians such as Ciona can regenerate the oral siphon and their central nervous system, and stem cells located in the branchial sac are required for this regeneration. Here, we summarize the cellular and molecular mechanisms of tunicate regeneration that have been identified so far and discuss differences and similarities between these mechanisms in regenerating tunicate species.
Topics: Animals; Central Nervous System; Epithelium; Regeneration; Stem Cells; Urochordata
PubMed: 30521811
DOI: 10.1016/j.ydbio.2018.11.021