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Signal Transduction and Targeted Therapy Jan 2024Although stem cell-based therapy has demonstrated considerable potential to manage certain diseases more successfully than conventional surgery, it nevertheless comes... (Review)
Review
Although stem cell-based therapy has demonstrated considerable potential to manage certain diseases more successfully than conventional surgery, it nevertheless comes with inescapable drawbacks that might limit its clinical translation. Compared to stem cells, stem cell-derived exosomes possess numerous advantages, such as non-immunogenicity, non-infusion toxicity, easy access, effortless preservation, and freedom from tumorigenic potential and ethical issues. Exosomes can inherit similar therapeutic effects from their parental cells such as embryonic stem cells and adult stem cells through vertical delivery of their pluripotency or multipotency. After a thorough search and meticulous dissection of relevant literature from the last five years, we present this comprehensive, up-to-date, specialty-specific and disease-oriented review to highlight the surgical application and potential of stem cell-derived exosomes. Exosomes derived from stem cells (e.g., embryonic, induced pluripotent, hematopoietic, mesenchymal, neural, and endothelial stem cells) are capable of treating numerous diseases encountered in orthopedic surgery, neurosurgery, plastic surgery, general surgery, cardiothoracic surgery, urology, head and neck surgery, ophthalmology, and obstetrics and gynecology. The diverse therapeutic effects of stem cells-derived exosomes are a hierarchical translation through tissue-specific responses, and cell-specific molecular signaling pathways. In this review, we highlight stem cell-derived exosomes as a viable and potent alternative to stem cell-based therapy in managing various surgical conditions. We recommend that future research combines wisdoms from surgeons, nanomedicine practitioners, and stem cell researchers in this relevant and intriguing research area.
Topics: Exosomes; Mesenchymal Stem Cells; Induced Pluripotent Stem Cells; Embryonic Stem Cells
PubMed: 38212307
DOI: 10.1038/s41392-023-01704-0 -
The Journal of Clinical Investigation Nov 2023Over the last decade, several organoid models have evolved to acquire increasing cellular, structural, and functional complexity. Advanced lung organoid platforms... (Review)
Review
Over the last decade, several organoid models have evolved to acquire increasing cellular, structural, and functional complexity. Advanced lung organoid platforms derived from various sources, including adult, fetal, and induced pluripotent stem cells, have now been generated, which more closely mimic the cellular architecture found within the airways and alveoli. In this regard, the establishment of novel protocols with optimized stem cell isolation and culture conditions has given rise to an array of models able to study key cellular and molecular players involved in lung injury and repair. In addition, introduction of other nonepithelial cellular components, such as immune, mesenchymal, and endothelial cells, and employment of novel precision gene editing tools have further broadened the range of applications for these systems by providing a microenvironment and/or phenotype closer to the desired in vivo scenario. Thus, these developments in organoid technology have enhanced our ability to model various aspects of lung biology, including pathogenesis of diseases such as chronic obstructive pulmonary disease, pulmonary fibrosis, cystic fibrosis, and infectious disease and host-microbe interactions, in ways that are often difficult to undertake using only in vivo models. In this Review, we summarize the latest developments in lung organoid technology and their applicability for disease modeling and outline their strengths, drawbacks, and potential avenues for future development.
Topics: Endothelial Cells; Induced Pluripotent Stem Cells; Lung; Pluripotent Stem Cells; Organoids
PubMed: 37966116
DOI: 10.1172/JCI170500 -
Advanced Science (Weinheim,... Jul 2023Over the last decade, adipose-derived stem cells (ADSCs) have attracted increasing attention in the field of regenerative medicine. ADSCs appear to be the most... (Review)
Review
Over the last decade, adipose-derived stem cells (ADSCs) have attracted increasing attention in the field of regenerative medicine. ADSCs appear to be the most advantageous cell type for regenerative therapies owing to their easy accessibility, multipotency, and active paracrine activity. This review highlights current challenges in translating ADSC-based therapies into clinical settings and discusses novel strategies to overcome the limitations of ADSCs. To further establish ADSC-based therapies as an emerging platform for regenerative medicine, this review also provides an update on the advancements in this field, including fat grafting, wound healing, bone regeneration, skeletal muscle repair, tendon reconstruction, cartilage regeneration, cardiac repair, and nerve regeneration. ADSC-based therapies are expected to be more tissue-specific and increasingly important in regenerative medicine.
Topics: Regenerative Medicine; Adipose Tissue; Adipocytes; Plastic Surgery Procedures; Stem Cells
PubMed: 37162248
DOI: 10.1002/advs.202207334 -
Nature Oct 2023The human embryo undergoes morphogenetic transformations following implantation into the uterus, but our knowledge of this crucial stage is limited by the inability to...
The human embryo undergoes morphogenetic transformations following implantation into the uterus, but our knowledge of this crucial stage is limited by the inability to observe the embryo in vivo. Models of the embryo derived from stem cells are important tools for interrogating developmental events and tissue-tissue crosstalk during these stages. Here we establish a model of the human post-implantation embryo, a human embryoid, comprising embryonic and extraembryonic tissues. We combine two types of extraembryonic-like cell generated by overexpression of transcription factors with wild-type embryonic stem cells and promote their self-organization into structures that mimic several aspects of the post-implantation human embryo. These self-organized aggregates contain a pluripotent epiblast-like domain surrounded by extraembryonic-like tissues. Our functional studies demonstrate that the epiblast-like domain robustly differentiates into amnion, extraembryonic mesenchyme and primordial germ cell-like cells in response to bone morphogenetic protein cues. In addition, we identify an inhibitory role for SOX17 in the specification of anterior hypoblast-like cells. Modulation of the subpopulations in the hypoblast-like compartment demonstrates that extraembryonic-like cells influence epiblast-like domain differentiation, highlighting functional tissue-tissue crosstalk. In conclusion, we present a modular, tractable, integrated model of the human embryo that will enable us to probe key questions of human post-implantation development, a critical window during which substantial numbers of pregnancies fail.
Topics: Female; Humans; Pregnancy; Bone Morphogenetic Proteins; Cell Differentiation; Embryo Implantation; Embryo, Mammalian; Embryoid Bodies; Embryonic Development; Germ Layers; Human Embryonic Stem Cells; Models, Biological; Transcription Factors; Pluripotent Stem Cells
PubMed: 37369347
DOI: 10.1038/s41586-023-06368-y -
Nature Sep 2023Vertebral bone is subject to a distinct set of disease processes from long bones, including a much higher rate of solid tumour metastases. The basis for this distinct...
Vertebral bone is subject to a distinct set of disease processes from long bones, including a much higher rate of solid tumour metastases. The basis for this distinct biology of vertebral bone has so far remained unknown. Here we identify a vertebral skeletal stem cell (vSSC) that co-expresses ZIC1 and PAX1 together with additional cell surface markers. vSSCs display formal evidence of stemness, including self-renewal, label retention and sitting at the apex of their differentiation hierarchy. vSSCs are physiologic mediators of vertebral bone formation, as genetic blockade of the ability of vSSCs to generate osteoblasts results in defects in the vertebral neural arch and body. Human counterparts of vSSCs can be identified in vertebral endplate specimens and display a conserved differentiation hierarchy and stemness features. Multiple lines of evidence indicate that vSSCs contribute to the high rates of vertebral metastatic tropism observed in breast cancer, owing in part to increased secretion of the novel metastatic trophic factor MFGE8. Together, our results indicate that vSSCs are distinct from other skeletal stem cells and mediate the unique physiology and pathology of vertebrae, including contributing to the high rate of vertebral metastasis.
Topics: Humans; Breast Neoplasms; Cell Differentiation; Cell Lineage; Cell Self Renewal; Neoplasm Metastasis; Osteoblasts; Spine; Stem Cells; Biomarkers
PubMed: 37704733
DOI: 10.1038/s41586-023-06519-1 -
Nature Aug 2023Cells undergo a major epigenome reconfiguration when reprogrammed to human induced pluripotent stem cells (hiPS cells). However, the epigenomes of hiPS cells and human...
Cells undergo a major epigenome reconfiguration when reprogrammed to human induced pluripotent stem cells (hiPS cells). However, the epigenomes of hiPS cells and human embryonic stem (hES) cells differ significantly, which affects hiPS cell function. These differences include epigenetic memory and aberrations that emerge during reprogramming, for which the mechanisms remain unknown. Here we characterized the persistence and emergence of these epigenetic differences by performing genome-wide DNA methylation profiling throughout primed and naive reprogramming of human somatic cells to hiPS cells. We found that reprogramming-induced epigenetic aberrations emerge midway through primed reprogramming, whereas DNA demethylation begins early in naive reprogramming. Using this knowledge, we developed a transient-naive-treatment (TNT) reprogramming strategy that emulates the embryonic epigenetic reset. We show that the epigenetic memory in hiPS cells is concentrated in cell of origin-dependent repressive chromatin marked by H3K9me3, lamin-B1 and aberrant CpH methylation. TNT reprogramming reconfigures these domains to a hES cell-like state and does not disrupt genomic imprinting. Using an isogenic system, we demonstrate that TNT reprogramming can correct the transposable element overexpression and differential gene expression seen in conventional hiPS cells, and that TNT-reprogrammed hiPS and hES cells show similar differentiation efficiencies. Moreover, TNT reprogramming enhances the differentiation of hiPS cells derived from multiple cell types. Thus, TNT reprogramming corrects epigenetic memory and aberrations, producing hiPS cells that are molecularly and functionally more similar to hES cells than conventional hiPS cells. We foresee TNT reprogramming becoming a new standard for biomedical and therapeutic applications and providing a novel system for studying epigenetic memory.
Topics: Humans; Cellular Reprogramming; Chromatin; DNA Demethylation; DNA Methylation; DNA Transposable Elements; Epigenesis, Genetic; Induced Pluripotent Stem Cells; Human Embryonic Stem Cells; Lamin Type B
PubMed: 37587336
DOI: 10.1038/s41586-023-06424-7 -
Cell Stem Cell Jan 2024All adult tissues experience wear and tear. Most tissues can compensate for cell loss through the activity of resident stem cells. Although the cellular maintenance... (Review)
Review
All adult tissues experience wear and tear. Most tissues can compensate for cell loss through the activity of resident stem cells. Although the cellular maintenance strategies vary greatly between different adult (read: postnatal) tissues, the function of stem cells is best defined by their capacity to replace lost tissue through division. We discuss a set of six complementary hallmarks that are key enabling features of this basic function. These include longevity and self-renewal, multipotency, transplantability, plasticity, dependence on niche signals, and maintenance of genome integrity. We discuss these hallmarks in the context of some of the best-understood adult stem cell niches.
Topics: Animals; Mammals; Stem Cell Niche; Stem Cells
PubMed: 38181752
DOI: 10.1016/j.stem.2023.12.006 -
Cell Stem Cell Mar 2024Mechanisms governing the maintenance of blood-producing hematopoietic stem and multipotent progenitor cells (HSPCs) are incompletely understood, particularly those...
Mechanisms governing the maintenance of blood-producing hematopoietic stem and multipotent progenitor cells (HSPCs) are incompletely understood, particularly those regulating fate, ensuring long-term maintenance, and preventing aging-associated stem cell dysfunction. We uncovered a role for transitory free cytoplasmic iron as a rheostat for adult stem cell fate control. We found that HSPCs harbor comparatively small amounts of free iron and show the activation of a conserved molecular response to limited iron-particularly during mitosis. To study the functional and molecular consequences of iron restriction, we developed models allowing for transient iron bioavailability limitation and combined single-molecule RNA quantification, metabolomics, and single-cell transcriptomic analyses with functional studies. Our data reveal that the activation of the limited iron response triggers coordinated metabolic and epigenetic events, establishing stemness-conferring gene regulation. Notably, we find that aging-associated cytoplasmic iron loading reversibly attenuates iron-dependent cell fate control, explicating intervention strategies for dysfunctional aged stem cells.
Topics: Hematopoiesis; Iron; Hematopoietic Stem Cells; Multipotent Stem Cells; Gene Expression Regulation; Cell Differentiation
PubMed: 38402617
DOI: 10.1016/j.stem.2024.01.011 -
Cellular & Molecular Immunology Jun 2023Mesenchymal stem/stromal cells (MSCs) are widely distributed in the body and play essential roles in tissue regeneration and homeostasis. MSCs can be isolated from... (Review)
Review
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.
Topics: Humans; Immunomodulation; Autoimmune Diseases; Umbilical Cord; Mesenchymal Stem Cells; Stem Cells; Mesenchymal Stem Cell Transplantation
PubMed: 36973490
DOI: 10.1038/s41423-023-00998-y -
Cell Feb 2024Human brain development involves an orchestrated, massive neural progenitor expansion while a multi-cellular tissue architecture is established. Continuously expanding...
Human brain development involves an orchestrated, massive neural progenitor expansion while a multi-cellular tissue architecture is established. Continuously expanding organoids can be grown directly from multiple somatic tissues, yet to date, brain organoids can solely be established from pluripotent stem cells. Here, we show that healthy human fetal brain in vitro self-organizes into organoids (FeBOs), phenocopying aspects of in vivo cellular heterogeneity and complex organization. FeBOs can be expanded over long time periods. FeBO growth requires maintenance of tissue integrity, which ensures production of a tissue-like extracellular matrix (ECM) niche, ultimately endowing FeBO expansion. FeBO lines derived from different areas of the central nervous system (CNS), including dorsal and ventral forebrain, preserve their regional identity and allow to probe aspects of positional identity. Using CRISPR-Cas9, we showcase the generation of syngeneic mutant FeBO lines for the study of brain cancer. Taken together, FeBOs constitute a complementary CNS organoid platform.
Topics: Humans; Brain; Central Nervous System; Extracellular Matrix; Organoids; Pluripotent Stem Cells; Prosencephalon; Tissue Culture Techniques; Stem Cells; Morphogenesis
PubMed: 38194967
DOI: 10.1016/j.cell.2023.12.012