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Mesenchymal stem cells (MSCs) are becoming hotspots for application in disease therapies recently, combining with biomaterials and drug delivery system. A major advantage of MSCs applied in drug delivery system is that these cells enable specific targeting and releasing of cargos to the disease sites. However, the potential tumor tropic effects of MSCs raised concerns on biosafety. To solve this problem, there are emerging methods of isolating cell membranes and developing nanoformulations to perform drug delivery, which avoids concerns on biosafety without disturbing the membrane functions of specific polarizing and locating. These cargoes are so called "nanoghosts." This review article summarizes the current applications of nanoghosts, the promising potential of MSCs to be applied in membrane isolation and nanoghost construction, and possible approaches to develop better drug delivery system harnessing from MSC ghost cell membranes.
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Células Madre Mesenquimatosas , Neoplasias , Humanos , Biomimética , Neoplasias/metabolismo , Sistemas de Liberación de Medicamentos , Membrana Celular , Células Madre Mesenquimatosas/metabolismoRESUMEN
The skin harbours transcriptionally and functionally heterogeneous mesenchymal cells that participate in various physiological activities by secreting biochemical cues. In this study, we aimed to identify a new subpopulation of dermal mesenchymal cells that enhance hair follicle regeneration through a paracrine mechanism. Integrated single-cell RNA sequencing (scRNA-seq) data analysis revealed epidermal growth factor receptor (EGFR) as a marker of distinct fibroblast subpopulation in the neonatal murine dermis. Immunofluorescence staining and fluorescence-activated cell sorting (FACS) were used to validate the existence of the cell population in Krt14-rtTA-H2BGFP mouse. The difference of gene expression between separated cell subpopulation was examined by real-time PCR. Potential effect of the designated factor on hair follicle regeneration was observed after the application on excisional wounds in Krt14-rtTA-H2BGFP mouse. Immunofluorescence staining demonstrated the existence of dermal EGFR+ cells in neonatal and adult mouse dermis. The EGFR+ mesenchymal population, sorted by FACS, displayed a higher expression level of Igf1 (insulin-like growth factor 1). Co-localisation of IGF1 with EGFR in the mouse dermis and upregulated numbers of hair follicles in healed wounds following the application of exogenous IGF1 illustrated the contribution of EGFR+ cells in promoting wound-induced hair follicle neogenesis. Our results indicate that EGFR identifies a subpopulation of dermal fibroblasts that contribute to IGF1 promotion of hair follicle neogenesis. It broadens the understanding of heterogeneity and the mesenchymal cell function in skin and may facilitate the potential translational application of these cells.
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Dermis , Folículo Piloso , Animales , Ratones , Dermis/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Folículo Piloso/fisiología , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , PielRESUMEN
The differentiation and maturation of mesenchymal stem cells (MSCs) to mesodermal and other lineages are known to be controlled by various extrinsic and intrinsic signals. The dysregulation of the MSC differentiation balance has been linked to several pathophysiological conditions, including obesity and osteoporosis. Previous research of the molecular mechanisms governing MSC differentiation has mostly focused on transcriptional regulation. However, recent findings are revealing the underrated role of alternative splicing (AS) in MSC differentiation and functions. In this review, we discuss recent progress in elucidating the regulatory roles of AS in MSC differentiation. We catalogue and highlight the key AS events that modulate MSC differentiation to major osteocytes, chondrocytes, and adipocytes, and discuss the regulatory mechanisms by which AS is regulated.
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Empalme Alternativo/genética , Diferenciación Celular/genética , Células Madre Mesenquimatosas/citología , Adipogénesis/genética , Animales , Condrogénesis/genética , Humanos , Células Madre Mesenquimatosas/metabolismo , Osteogénesis/genéticaRESUMEN
Despite the long discrepancy over their definition, heterogeneity, and functions, mesenchymal stem cells (MSCs) have proved to be a key player in tissue repair and homeostasis. Generally, somatic tissue-derived MSCs (st-MSCs) are subject to quality variations related to donated samples and biosafety concern for transmission of potential pathogens from the donors. In contrast, human pluripotent stem cells (hPSCs) are unlimited in supply, clear in the biological background, and convenient for quality control, genetic modification, and scale-up production. We, and others, have shown that hPSCs can differentiate in two dimensions or three dimensions to MSCs (ps-MSCs) via embryonic (mesoderm and neural crest) or extraembryonic (trophoblast) cell types under serum-containing or xeno-free and defined conditions. Compared to st-MSCs, ps-MSCs appear less mature, proliferate faster, express lower levels of inflammatory cytokines, and respond less to traditional protocols for st-MSC differentiation to other cell types, especially adipocytes. Nevertheless, ps-MSCs are capable of immune modulation and treatment of an increasing number of animal disease models via mitochondria transfer, paracrine, exosomes, and direct differentiation, and can be potentially used as a universal and endless therapy for clinical application. This review summarizes the progress on ps-MSCs and discusses perspectives and challenges for their potential translation to the clinic. Stem Cells 2019;37:572-581.
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Tratamiento Basado en Trasplante de Células y Tejidos , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Células Madre Pluripotentes/trasplante , Adipocitos/citología , Proliferación Celular/genética , HumanosRESUMEN
With ongoing clinical trials, human embryonic stem cells (hESCs) have shown substantial potential for regenerative medicine. However, due to the mismatch of human leukocyte antigens (HLAs) between hESC-derived allografts and recipients, immunosuppressant regimens must be used to prevent immune rejection of the grafts. Considerable efforts have been devoted to overcoming this hurdle via the derivation and banking of human nuclear transfer ESCs, parthenogenetic ESCs, and induced pluripotent stem cells. However, ethical and safety concerns remain, hindering the application of these types of pluripotent cells. Other approaches have recently been explored to generate universally compatible hESCs through the silencing or deletion of HLAs or genes essential for HLA expression, including ß-2-microglobulin and class-II MHC transactivator, as well as the induction of immunosuppression via the ectopic expression of non-classical HLAs (e.g., HLA-E and -G), cytotoxic T lymphocyte antigen 4 fused with immunoglobulin, and programmed death ligand-1. In this review, we introduce developments in this line of research and discuss strategies to reduce the tumorigenic concerns regarding hESCs, especially after they acquire the capability to escape immune surveillance. Stem Cells 2016;34:2269-2275.
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Técnicas de Cultivo de Célula/métodos , Células Madre Embrionarias Humanas/citología , Carcinogénesis/patología , Células Madre Embrionarias Humanas/inmunología , Humanos , Terapia de Inmunosupresión , Cordón Umbilical/citologíaRESUMEN
Mesenchymal stem/stromal cells (MSCs) have great clinical potential in modulating inflammation and promoting tissue repair. Human embryonic stem cells (hESCs) have recently emerged as a potentially superior cell source for MSCs. However, the generation methods reported so far vary greatly in quality and efficiency. Here, we describe a novel method to rapidly and efficiently produce MSCs from hESCs via a trophoblast-like intermediate stage in approximately 11-16 days. We term these cells "T-MSCs" and show that T-MSCs express a phenotype and differentiation potential minimally required to define MSCs. T-MSCs exhibit potent immunomodulatory activity in vitro as they can remarkably inhibit proliferation of cocultured T and B lymphocytes. Unlike bone marrow MSCs, T-MSCs do not have increased expression of inflammatory mediators in response to IFNγ. Moreover, T-MSCs constitutively express a high level of the immune inhibitory ligand PD-L1 and elicit strong and durable efficacy in two distinct animal models of autoimmune disease, dextran sulfate sodium induced colitis, and experimental autoimmune encephalomyelitis, at doses near those approved for clinical trials. Together, we present a simple and fast derivation method to generate MSCs from hESCs, which possess potent immunomodulatory properties in vitro and in vivo and may serve as a novel and ideal candidate for MSC-based therapies.
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Diferenciación Celular/inmunología , Proliferación Celular , Células Madre Embrionarias Humanas/inmunología , Inmunomodulación , Células Madre Mesenquimatosas/inmunología , Trofoblastos/inmunología , Células Madre Embrionarias Humanas/citología , Humanos , Células Madre Mesenquimatosas/citología , Trofoblastos/citologíaRESUMEN
It has been recently reported that the regulatory circuitry formed by OCT4, miR-302, and NR2F2 controls both pluripotency and neural differentiation of human embryonic stem cells (hESCs). We show here that JMJD1C, a histone 3 lysine 9 (H3K9) demethylase expressed in hESCs, directly interacts with this circuitry. hESCs with stable knockdown of JMJD1C remain pluripotent while having reduced miR-302 expression, decreased BMP signaling, and enhanced TGFß signaling. JMJD1C binds to the miR-302 promoter and reduces H3K9 methylation. Withdrawal of basic fibroblast growth factor (bFGF) from the culture induces neural differentiation of the knockdown, but not the control, cells within 3 days, accompanied by elevated NR2F2 expression. This can be attenuated with miR-302 mimics or an H3K9 methytransferase inhibitor. Together, our findings suggest that JMJD1C represses neural differentiation of hESCs at least partially by epigenetically sustaining miR-302 expression and that JMJD1C knockdown is sufficient to trigger neural differentiation upon withdrawal of exogenous bFGF.
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Diferenciación Celular/fisiología , Células Madre Embrionarias/metabolismo , Epigénesis Genética/fisiología , Histona Demetilasas con Dominio de Jumonji/metabolismo , MicroARNs/biosíntesis , Oxidorreductasas N-Desmetilantes/metabolismo , Transducción de Señal/fisiología , Proteínas Morfogenéticas Óseas/genética , Proteínas Morfogenéticas Óseas/metabolismo , Factor de Transcripción COUP I/genética , Factor de Transcripción COUP I/metabolismo , Línea Celular , Células Madre Embrionarias/citología , Factor 2 de Crecimiento de Fibroblastos/genética , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Humanos , Histona Demetilasas con Dominio de Jumonji/genética , MicroARNs/genética , Neuronas/citología , Neuronas/metabolismo , Oxidorreductasas N-Desmetilantes/genética , Regiones Promotoras Genéticas/fisiología , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
[This corrects the article DOI: 10.3389/fimmu.2023.1131985.].
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Circulating tumor cells (CTCs) shed from primary tumors must overcome the cytotoxicity of immune cells, particularly natural killer (NK) cells, to cause metastasis. The tumor microenvironment (TME) protects tumor cells from the cytotoxicity of immune cells, which is partially executed by cancer-associated mesenchymal stromal cells (MSCs). However, the mechanisms by which MSCs influence the NK resistance of CTCs remain poorly understood. This study demonstrates that MSCs enhance the NK resistance of cancer cells in a gap junction-dependent manner, thereby promoting the survival and metastatic seeding of CTCs in immunocompromised mice. Tumor cells crosstalk with MSCs through an intercellular cGAS-cGAMP-STING signaling loop, leading to increased production of interferon-ß (IFNß) by MSCs. IFNß reversely enhances the type I IFN (IFN-I) signaling in tumor cells and hence the expression of human leukocyte antigen class I (HLA-I) on the cell surface, protecting the tumor cells from NK cytotoxicity. Disruption of this loop reverses NK sensitivity in tumor cells and decreases tumor metastasis. Moreover, there are positive correlations between IFN-I signaling, HLA-I expression, and NK tolerance in human tumor samples. Thus, the NK-resistant signaling loop between tumor cells and MSCs may serve as a novel therapeutic target.
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Interferón beta , Células Asesinas Naturales , Células Madre Mesenquimatosas , Células Neoplásicas Circulantes , Nucleotidiltransferasas , Transducción de Señal , Microambiente Tumoral , Células Madre Mesenquimatosas/inmunología , Células Madre Mesenquimatosas/metabolismo , Animales , Células Asesinas Naturales/inmunología , Ratones , Interferón beta/metabolismo , Interferón beta/inmunología , Nucleotidiltransferasas/metabolismo , Nucleotidiltransferasas/genética , Humanos , Células Neoplásicas Circulantes/inmunología , Células Neoplásicas Circulantes/metabolismo , Microambiente Tumoral/inmunología , Proteínas de la Membrana/metabolismo , Modelos Animales de Enfermedad , Línea Celular TumoralRESUMEN
Induced pluripotent stem cells (iPSC) hold tremendous potential for personalized cell-based repair strategies to treat musculoskeletal disorders. To establish human iPSCs as a potential source of viable chondroprogenitors for articular cartilage repair, we assessed the in vitro chondrogenic potential of the pluripotent population versus an iPSC-derived mesenchymal-like progenitor population. We found the direct plating of undifferentiated iPSCs into high-density micromass cultures in the presence of BMP-2 promoted chondrogenic differentiation, however these conditions resulted in a mixed population of cells resembling the phenotype of articular cartilage, transient cartilage, and fibrocartilage. The progenitor cells derived from human iPSCs exhibited immunophenotypic features of mesenchymal stem cells (MSCs) and developed along multiple mesenchymal lineages, including osteoblasts, adipocytes, and chondrocytes in vitro. The data indicate the derivation of a mesenchymal stem cell population from human iPSCs is necessary to limit culture heterogeneity as well as chondrocyte maturation in the differentiated progeny. Moreover, as compared to pellet culture differentiation, BMP-2 treatment of iPSC-derived MSC-like (iPSC-MSC) micromass cultures resulted in a phenotype more typical of articular chondrocytes, characterized by the enrichment of cartilage-specific type II collagen (Col2a1), decreased expression of type I collagen (Col1a1) as well as lack of chondrocyte hypertrophy. These studies represent a first step toward identifying the most suitable iPSC progeny for developing cell-based approaches to repair joint cartilage damage.
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Cartílago Articular , Diferenciación Celular , Células Madre Pluripotentes Inducidas , Células Madre Mesenquimatosas , Adipocitos/citología , Adipocitos/metabolismo , Proteína Morfogenética Ósea 2/administración & dosificación , Proteína Morfogenética Ósea 2/metabolismo , Huesos/citología , Huesos/metabolismo , Cartílago Articular/citología , Cartílago Articular/metabolismo , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Linaje de la Célula , Células Cultivadas , Condrocitos/citología , Condrocitos/metabolismo , Condrogénesis/efectos de los fármacos , Colágeno Tipo II/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacosRESUMEN
The usefulness of human induced pluripotent stem cells (hiPSCs) in research and therapeutic applications highly relies on their genomic integrity and stability. Many laboratories including ours have addressed this concern by comparing genomic (at both karyotypic and subkaryotypic levels) and epigenomic abnormalities of hiPSC lines (derived via either DNA- or non-DNA-based methods), as well as human embryonic stem cell lines during long-term culture. A variety of methods have been used for this purpose, such as karyotyping and fluorescent in situ hybridization to detect karyotypic abnormalities, array-based comparative genomic hybridization to detect copy number variations (CNVs), single-nucleotide polymorphism-based microarrays to detect both CNVs and loss of heterozygosity, analysis of integration sites in the genome, and whole genome sequencing for protein-coding exome and DNA methylome profiling. Here, we summarize the progresses in this dynamically evolving field and also discuss how the findings apply to the study and application of hiPSCs.
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Inestabilidad Genómica , Células Madre Pluripotentes Inducidas/metabolismo , Línea Celular , Variaciones en el Número de Copia de ADN/genética , Células Madre Embrionarias/metabolismo , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
The pilosebaceous unit (PSU) is composed of multiple compartments and the self-renewal of PSU depends on distinct hair follicle stem cell (HFSC) populations. However, the differential roles of the HFSCs in sebaceous gland (SG) renewal have not been completely understood. Here, we performed multiple lineage tracing analysis to unveil the contribution of different HFSC populations to PSU regeneration during the hair cycle and wound healing. Our results indicated that the upper bulge stem cells contributed extensively to the SG replenishment during hair cycling, while HFSCs in the lower bugle did not. During skin wound healing, all HFSC populations participated in the SG replenishment. Moreover, ß-catenin activation promoted the contribution of HFSCs to SG replenishment, whereas ß-catenin deletion substantially repressed the event. Thus, our findings indicated that HFSCs contributed to SG replenishment in a ß-catenin-dependent manner.
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Mesenchymal stem cells (MSCs) are present in almost all the tissues in the body, critical for their homeostasis and regeneration. However, the stemness of MSCs is mainly an in vitro observation, and lacking exclusive markers for endogenous MSCs makes it difficult to study the multipotency of MSCs in vivo, especially for human MSCs. To address this hurdle, we injected GFP-tagged human embryonic stem cell (hESC)-derived MSCs (EMSCs) into mouse blastocysts. EMSCs survived well and penetrated both the inner cell mass and trophectoderm, correlating to the higher anti-apoptotic capability of EMSCs than hESCs. Injected EMSCs contributed to skeletal, dermal, and extraembryonic tissues in the resultant chimera and partially rescued skeletal defects in Sox9+/- mouse fetuses. Thus, this study provides evidence for the stemness and developmental capability of human MSCs through chimerization with the mouse blastocyst, serving as a model for studying human mesenchymal and skeletal development.
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Células Madre Embrionarias Humanas , Células Madre Mesenquimatosas , Humanos , Ratones , Animales , Diferenciación Celular , Células Madre Embrionarias , BlastocistoRESUMEN
The treatment of refractory cutaneous wounds remains to be a clinical challenge. There is growing evidence to show that mesenchymal stem cells (MSCs) have great potential in promoting wound healing. However, the therapeutic effects of MSCs are greatly dampened by their poor survival and engraftment in the wounds. To address this limitation, in this study, MSCs were grown into a collagen-glycosaminoglycan (C-GAG) matrix to form a dermis-like tissue sheet, named engineered dermal substitute (EDS). When seeded on C-GAG matrix, MSCs adhered rapidly, migrated into the pores, and proliferated readily. When applied onto excisional wounds in healthy and diabetic mice, the EDS survived well, and accelerated wound closure, compared with C-GAG matrix alone or MSCs in collagen hydrogel. Histological analysis revealed that EDS prolonged the retention of MSCs in the wounds, associated with increased macrophage infiltration and enhanced angiogenesis. RNA-Seq analysis of EDS-treated wounds uncovered the expression of abundant human chemokines and proangiogenic factors and their corresponding murine receptors, suggesting a mechanism of ligand/receptor-mediated signals in wound healing. Thus, our results indicate that EDS prolongs the survival and retention of MSCs in the wounds and enhances wound healing.
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Diabetes Mellitus Experimental , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Ratones , Humanos , Animales , Diabetes Mellitus Experimental/metabolismo , Cicatrización de Heridas , Células Madre Mesenquimatosas/metabolismo , Trasplante de Células Madre Mesenquimatosas/métodosRESUMEN
The mRNA vaccines (RVs) can reduce the severity and mortality of severe acute respiratory syndrome coronavirus (SARS-CoV-2). However, almost only the inactivated vaccines (IVs) but no RVs had been used in mainland China until most recently, and the relaxing of its anti-pandemic strategies in December 2022 increased concerns about new outbreaks. In comparison, many of the citizens in Macao Special Administrative Region of China received three doses of IV (3IV) or RV (3RV), or 2 doses of IV plus one booster of RV (2IV+1RV). By the end of 2022, we recruited 147 participants with various vaccinations in Macao and detected antibodies (Abs) against the spike (S) protein and nucleocapsid (N) protein of the virus as well as neutralizing antibodies (NAb) in their serum. We observed that the level of anti-S Ab or NAb was similarly high with both 3RV and 2IV+1RV but lower with 3IV. In contrast, the level of anti-N Ab was the highest with 3IV like that in convalescents, intermediate with 2IV+1RV, and the lowest with 3RV. Whereas no significant differences in the basal levels of cytokines related to T-cell activation were observed among the various vaccination groups before and after the boosters. No vaccinees reported severe adverse events. Since Macao took one of the most stringent non-pharmaceutical interventions in the world, this study possesses much higher confidence in the vaccination results than many other studies from highly infected regions. Our findings suggest that the heterologous vaccination 2IV+1RV outperforms the homologous vaccinations 3IV and 3RV as it induces not only anti-S Ab (to the level as with 3RV) but also anti-N antibodies (via the IV). It combines the advantages of both RV (to block the viral entry) and IV (to also intervene the subsequent pathological processes such as intracellular viral replication and interference with the signal transduction and hence the biological functions of host cells).
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COVID-19 , Proteínas de la Nucleocápside , Humanos , Macao , SARS-CoV-2 , Vacunas de Productos Inactivados , COVID-19/prevención & control , Anticuerpos Neutralizantes , Vacunas de ARNmRESUMEN
Mesenchymal stem/Stromal cells (MSCs) have great therapeutic potentials, and they have been isolated from various tissues and organs including definitive endoderm (DE) organs, such as the lung, liver and intestine. MSCs have been induced from human pluripotent stem cells (hPSCs) through multiple embryonic lineages, including the mesoderm, neural crest, and extraembryonic cells. However, it remains unclear whether hPSCs could give rise to MSCs in vitro through the endodermal lineage. Here, we report that hPSC-derived, SOX17+ definitive endoderm progenitors can further differentiate to cells expressing classic MSC markers, which we name definitive endoderm-derived MSCs (DE-MSCs). Single cell RNA sequencing demonstrates the stepwise emergence of DE-MSCs, while endoderm-specific gene expression can be elevated by signaling modulation. DE-MSCs display multipotency and immunomodulatory activity in vitro and possess therapeutic effects in a mouse ulcerative colitis model. This study reveals that, in addition to the other germ layers, the definitive endoderm can also contribute to MSCs and DE-MSCs could be a cell source for regenerative medicine.
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Células Madre Mesenquimatosas , Células Madre Pluripotentes , Animales , Ratones , Humanos , Diferenciación Celular/genética , Células Madre Mesenquimatosas/metabolismo , Hígado , MesodermoRESUMEN
COVID-19 is hopefully approaching its end in many countries as herd immunity develops and weaker strains of SARS-CoV-2 dominate. However, a new concern occurs over the long-term effects of COVID-19, collectively called "Long COVID", as some symptoms of the nervous system last even after patients recover from COVID-19. This review focuses on studies of anosmia, i.e., impairment of smell, which is the most common sensory defect during the disease course and is caused by olfactory dysfunctions. It remains mysterious how the olfactory functions are affected since the virus can't invade olfactory receptor neurons. We describe several leading hypotheses about the mystery in hope to provide insights into the pathophysiology and treatment strategies for anosmia.
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Anosmia , COVID-19 , Anosmia/diagnóstico , Anosmia/virología , COVID-19/complicaciones , Humanos , SARS-CoV-2 , Síndrome Post Agudo de COVID-19RESUMEN
Mesenchymal stem cells (MSCs) as a therapeutic promise are often quickly cleared by innate immune cells of the host including natural killer (NK) cells. Efforts have been made to generate immune-escaping human embryonic stem cells (hESCs) where T cell immunity is evaded by defecting ß-2-microglobulin (B2M), a common unit for human leukocyte antigen (HLA) class I, and NK cells are inhibited via ectopic expression of HLA-E or -G. However, NK subtypes vary among recipients and even at different pathologic statuses. It is necessary to dissect and optimize the efficacy of the immune-escaping cells against NK subtypes. Here, we first generated B2M knockout hESCs and differentiated them to MSCs (EMSCs) and found that NK resistance occurred with B2M-/- EMSCs expressing HLA-E and -G only when they were transduced via an inducible lentiviral system in a dose-dependent manner but not when they were inserted into a safe harbor. HLA-E and -G expressed at high levels together in transduced EMSCs inhibited three major NK subtypes, including NKG2A+ /LILRB1+ , NKG2A+ /LILRB1- , and NKG2A- /LILRB1+ , which was further potentiated by IFN-γ priming. Thus, this study engineers MSCs with resistance to multiple NK subtypes and underscores that dosage matters when a transgene is used to confer a novel effect to host cells, especially for therapeutic cells to evade immune rejection.
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Células Asesinas Naturales/inmunología , Células Madre Mesenquimatosas/inmunología , Ingeniería de Tejidos/métodos , Microglobulina beta-2/inmunología , Línea Celular , HumanosRESUMEN
We have previously demonstrated that mesenchymal stromal/stem cells (MSCs) in spheroids (MSCsp) tolerate ambient and hypoxic conditions for a prolonged time. Local administration of MSCsp, but not dissociated MSCs (MSCdiss), promotes wound healing and relieves multiple sclerosis and osteoarthritis in mice and monkeys. These findings indicate an advantage of MSCsp over MSCdiss in sustaining cell viability and efficacy following transplantation, which, however, does not appear to apply to intravenous (i.v.) injection for the principal concern that MSCsp might cause embolism in small blood vessels of the host, leading to sudden death. Here, we addressed this concern by injecting human MSCsp (â¼450 µm) or MSCdiss i.v. into cynomolgus monkeys. Surprisingly, no deaths occurred until sacrifice at day 21 or 60 post injection, and no remarkable physiological changes were found in the animals following the i.v. injection. The big diameters of large blood vessels in monkeys, compared to small animals like mice, may allow sufficient time for MSCsp to dissociate into single cells so they can pass through small vessels without causing embolism. Retention of MSCsp was lower in the lungs but higher in the blood than retention of MSCdiss at 1 h post injection and both disappeared at day 21. In vitro, MSCsp tolerated fluidic shear stress with higher survival than MSCdiss. Thus, i.v. injection of MSCsp into nonhuman primates is feasible, safe, and probably associated with better survival, less lung entrapment and higher efficacy than administration of MSCdiss.
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Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Osteoartritis , Animales , Humanos , Inyecciones Intravenosas , Macaca fascicularis , Ratones , Osteoartritis/metabolismoRESUMEN
The Coronavirus disease-19 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus -2 (SARS-CoV-2), has impacted human lives in the most profound ways with millions of infections and deaths. Scientists and pharmaceutical companies have been in race to produce vaccines against SARS-CoV-2. Vaccine generation usually demands years of developing and testing for efficacy and safety. However, it only took less than one year to generate two mRNA vaccines from their development to deployment. The rapid production time, cost-effectiveness, versatility in vaccine design, and clinically proven ability to induce cellular and humoral immune response have crowned mRNA vaccines with spotlights as most promising vaccine candidates in the fight against the pandemic. In this review, we discuss the general principles of mRNA vaccine design and working mechanisms of the vaccines, and provide an up-to-date summary of pre-clinical and clinical trials on seven anti-COVID-19 mRNA candidate vaccines, with the focus on the two mRNA vaccines already licensed for vaccination. In addition, we highlight the key strategies in designing mRNA vaccines to maximize the expression of immunogens and avoid intrinsic innate immune response. We also provide some perspective for future vaccine development against COVID-19 and other pathogens.