Stem Cells Translational Medicine最新文献

Mesenchymal stromal/stem cells (MSCs) are promising candidates for regenerative medicine owing to their self-renewal properties, multilineage differentiation, immunomodulatory effects, and angiogenic potential. MSC spheroids fabricated by 3D culture have recently shown enhanced therapeutic potential. MSC spheroids create a specialized niche with tight cell-cell and cell-extracellular matrix interactions, optimizing their cellular function by mimicking the in vivo environment. Methods for 3D cultivation of MSCs can be classified into 2 main forms: static suspension culture and dynamic suspension culture. Numerous studies have reported the beneficial influence of these methods on MSCs, which is displayed by increased differentiation, angiogenic, immunomodulatory, and anti-apoptotic effects, and stemness of MSC spheroids. Particularly, recent studies highlighted the benefits of dynamic suspension cultures of the MSC spheroids in terms of faster and more compact spheroid formation and the long-term maintenance of stemness properties. However, only a few studies have compared the behavior of MSC spheroids formed using static and dynamic suspension cultures, considering the significant differences between their culture conditions. This review summarizes the differences between static and dynamic suspension culture methods and discusses the biological outcomes of MSC spheroids reported in the literature. In particular, we highlight the advantages of the dynamic suspension culture of MSC spheroids and contemplate its future applications for various diseases.

The use of dental implants to replace lost or damaged teeth has become increasingly widespread due to their reported high survival and success rates. In reality, the long-term survival of dental implants remains a health concern, based on their short-term predicted survival of ~15 years, significant potential for jawbone resorption, and risk of peri-implantitis. The ability to create functional bioengineered teeth, composed of living tissues with properties similar to those of natural teeth, would be a significant improvement over currently used synthetic titanium implants. To address this possibility, our research has focused on creating biological tooth substitutes. The study presented here validates a potentially clinically relevant bioengineered tooth replacement therapy for eventual use in humans. We created bioengineered tooth buds by seeding decellularized tooth bud (dTB) extracellular matrix (ECM) scaffolds with human dental pulp cells, porcine tooth bud-derived dental epithelial cells, and human umbilical vein endothelial cells. The resulting bioengineered tooth bud constructs were implanted in the mandibles of adult Yucatan minipigs and grown for 2 or 4 months. We observed the formation of tooth-like tissues, including tooth-supporting periodontal ligament tissues, in cell-seeded dTB ECM constructs. This preclinical translational study validates this approach as a potential clinically relevant alternative to currently used dental implants.

Retinal pigment epithelium (RPE) atrophy is a significant cause of human blindness worldwide, occurring in polygenic diseases such as age-related macular degeneration (AMD) and monogenic diseases such as Stargardt diseases (STGD1) and late-onset retinal degeneration (L-ORD). The patient-induced pluripotent stem cells (iPSCs)-derived RPE (iRPE) model exhibits many advantages in understanding the cellular basis of pathological mechanisms of RPE atrophy. The iRPE model is based on iPSC-derived functionally mature and polarized RPE cells that reproduce several features of native RPE cells, such as phagocytosis of photoreceptor outer segments (POS) and replenishment of visual pigment. When derived from patients, iRPE are able to recapitulate critical cellular phenotypes of retinal degenerative diseases, such as the drusen-like sub-RPE deposits in the L-ORD and AMD models; lipid droplets and cholesterol accumulation in the STGD1 and AMD models. The iRPE model has helped discover the unexpected role of RPE in understanding retinal degenerative diseases, such as a cell-autonomous function of ABCA4 in STGD1. The iRPE model has helped uncover the pathological mechanism of retinal degenerative diseases, including the roles of alternate complement cascades and oxidative stress in AMD pathophysiology, abnormal POS processing in STGD1 and L-ORD, and its association with lipid accumulation. These studies have helped better understand-the role of RPE in retinal degenerative diseases, and molecular mechanisms underlying RPE atrophy, and have provided a basis to discover therapeutics to target RPE-associated diseases.

Extracellular vesicles (EVs) are evolutionarily conserved communication mediators that play key roles in the development of periodontal disease as well as in regeneration processes. This concise review first outlines the pathogenic mechanisms through which EVs derived from bacteria lead to the progression of periodontitis, with a focus on the enrichment of virulence factors, the amplification of immune responses, and the induction of bone destruction as key aspects influenced by bacterial EVs. This review aims to elucidate the positive effects of EVs derived from mesenchymal stem cells (MSC-EVs) on periodontal tissue regeneration. In particular, the anti-inflammatory properties of MSC-EVs and their impact on the intricate interplay between MSCs and various immune cells, including macrophages, dendritic cells, and T cells, are described. Moreover, recent advancements regarding the repair-promoting functions of MSC-EVs are detailed, highlighting the mechanisms underlying their ability to promote osteogenesis, cementogenesis, angiogenesis, and the homing of stem cells, thus contributing significantly to periodontal tissue regeneration. Furthermore, this review provides insights into the therapeutic efficacy of MSC-EVs in treating periodontitis within a clinical context. By summarizing the current knowledge, this review aims to provide a comprehensive understanding of how MSC-EVs can be harnessed for the treatment of periodontal diseases. Finally, a discussion is presented on the challenges that lie ahead and the potential practical implications for translating EV-based therapies into clinical practices for the treatment of periodontitis.

ATP is present in negligible concentrations in the interstitium of healthy tissues but accumulates to significantly higher concentrations in an inflammatory microenvironment. ATP binds to 2 categories of purine receptors on the surface of cells, the ionotropic P2X receptors and metabotropic P2Y receptors. Included in the family of ionotropic purine receptors is P2X7 (P2X7R), a non-specific cation channel with unique functional and structural properties that suggest it has distinct roles in pathological conditions marked by increased extracellular ATP. The role of P2X7R has previously been explored in microglia and astrocytes within the context of neuroinflammation, however the presence of P2X7R on human motor neurons and its potential role in neurodegenerative diseases has not been the focus of the current literature. We leveraged the use of human iPSC-derived spinal motor neurons (hiPSC-MN) as well as human and rodent tissue to demonstrate the expression of P2X7R on motor neurons. We extend this observation to demonstrate that these receptors are functionally active on hiPSC-MN and that ATP can directly induce death via P2X7R activation in a dose dependent manner. Finally, using a highly specific P2X7R blocker, we demonstrate how modulation of P2X7R activation on motor neurons is neuroprotective and could provide a unique pharmacologic target for ATP-induced MN death that is distinct from the role of ATP as a modulator of neuroinflammation.

In the treatment of cartilage defects, a key factor is the adequate and specific recruitment of endogenous stem cells to the site of injury. However, the limited quantity and capability of endogenous bone marrow stem cells (BM MSCs) often result in the formation of fibrocartilage when using bone marrow stimulation (BMS) procedures. We engineered second-generation platelet-rich plasma (2G PRP) with defibrinogenating and antifibrinolytic agents for injection into the condyle of the right femur, followed by multiple channeling (MCh) 5 days later. This approach aims to enhance repair by promoting the local proliferation and migration of BM MSCs to the full-thickness knee cartilage defect (ftKD). In our in vitro study, 2G PRP increased the number of endogenous BM MSCs and their ability to migrate toward an IL-1β-induced inflammatory condition. This significance was further confirmed by in vivo proliferation results after injection of 2G PRP into the condyle of rats. Fifty-four healthy male Sprague-Dawley rats were divided into 3 groups (ftKD, MCh, 2G MCh) for 3 time points (2 weeks, 4 weeks, 8 weeks). The 2G MCh (2G PRP injection + MCh) groups significantly improved cartilage formation at 4 and 8 weeks compared to the ftKD and MCh groups. The 2G MCh initiated cartilage repair earlier than MCh and significantly enhanced up to 8 weeks. This study demonstrated that 2G PRP increased the number of BM MSCs through the enhancement of proliferation and recruitment into the injured site, thereby improving articular cartilage repair.

Research conducted on the International Space Station (ISS) in low-Earth orbit (LEO) has shown the effects of microgravity on multiple organs. To investigate the effects of microgravity on the central nervous system, we developed a unique organoid strategy for modeling specific regions of the brain that are affected by neurodegenerative diseases. We generated 3-dimensional human neural organoids from induced pluripotent stem cells (iPSCs) derived from individuals affected by primary progressive multiple sclerosis (PPMS) or Parkinson's disease (PD) and non-symptomatic controls, by differentiating them toward cortical and dopaminergic fates, respectively, and combined them with isogenic microglia. The organoids were cultured for a month using a novel sealed cryovial culture method on the International Space Station (ISS) and a parallel set that remained on Earth. Live samples were returned to Earth for analysis by RNA expression and histology and were attached to culture dishes to enable neurite outgrowth. Our results show that both cortical and dopaminergic organoids cultured in LEO had lower levels of genes associated with cell proliferation and higher levels of maturation-associated genes, suggesting that the cells matured more quickly in LEO. This study is continuing with several more missions in order to understand the mechanisms underlying accelerated maturation and to investigate other neurological diseases. Our goal is to make use of the opportunity to study neural cells in LEO to better understand and treat neurodegenerative disease on Earth and to help ameliorate potentially adverse neurological effects of space travel.

Mesenchymal stem cells (MSCs) are multipotent cells with high self-renewal and multilineage differentiation abilities, playing an important role in tissue healing. Recent advancements in stem cell-based technologies have offered new and promising therapeutic options in regenerative medicine. Upon tissue damage, MSCs are immediately mobilized from the bone marrow and move to the injury site via blood circulation. Notably, allogenically transplanted MSCs can also home to the damaged tissue site. Therefore, MSCs hold great therapeutic potential for curing various diseases. However, one major obstacle to this approach is attracting MSCs specifically to the injury site following systemic administration. In this review, we describe the molecular pathways governing the homing mechanism of MSCs and various strategies for improving this process, including targeted stem cell administration, target tissue modification, in vitro priming, cell surface engineering, genetic modifications, and magnetic guidance. These strategies are crucial for directing MSCs precisely to the injury site and, consequently, enhancing their migration and local tissue repair properties. Specifically, our review provides a guide to improving the therapeutic efficacy of clinical applications of MSCs through optimized in vivo administration and homing capacities.