The versatility of mesenchymal stem cells: From regenerative medicine to COVID,what is next?

Mesenchymal stem cells (MSCs) play key roles in regenerative medicine by promoting tissue healing. MSCs can be isolated from different adult tissues and they are able to differentiate into several lineages. Due to their anti-inflammatory, angiogenic and immune-modulatory properties, MSCs are suitable for tissue engineering applications and, when associated with biomaterials, their benefits can be improved. Moreover, recently, MSCs have been studied for new clinical applications, such as in the treatment of patients with COVID-19. MSCs regenerative potential has been attributed to their secretome, which comprises extracellular matrix, soluble proteins and several elements, including the release of extracellular vesicles. Even though, in order to explore all their therapeutic potential, it is still necessary to advance in the investigation of their basic cell biology characteristics.     

Controversies in therapeutic application of mesenchymal stem cell-derived secretome

Though mesenchymal stem cells (MSCs) are considered as an important pillar of regenerative medicine, their regenerative potential has been shown to be limited in several pathological conditions. The adverse properties of MSC-based cell therapy have drawn attention to the therapeutic use of MSC-derived secretome. However, MSC-originated exosomes and microvesicles can also possess a significant impact on disease development, including cancer. By interchanging secretome, MSCs can interact with tumor cells and promote mutual exchange/induction of cellular markers. In addition, enzymes secreted into and activated within exosomes can result in the acquisition of new tumor cell properties. Therefore, therapeutic applications of MSC-derived secretome require much caution.     

Production of mesenchymal stem cell derived-secretome as cell-free regenerative therapy and immunomodulation: A biomanufacturing perspective

The potential of mesenchymal stem cells (MSCs) in regenerative medicine has been largely known due to their capability to induce tissue regeneration in vivo with minimum inflammation during implantation. This adult stem cell type exhibit unique features of tissue repair mechanism and immune modulation mediated by their secreted factors, called secretome. Recently, the utilization of secretome as a therapeutic agent provided new insight into cell-free therapy. Nevertheless, a sufficient amount of secretome is necessary to realize their applications for translational medicine which required a proper biomanufacturing process. Several factors related to their production need to be considered to produce a clinical-grade secretome as a biological therapeutic agent. This viewpoint highlights the current challenges and considerations during the biomanufacturing process of MSCs secretome.     

Therapeutic mechanisms and routes of delivery of mesenchymal stem cells in veterinary medicine: A point of view

Mesenchymal stem cells (MSCs) represent an important tool in veterinary regenerative medicine due to their ability to home to injury sites and secrete molecules that regulate niches into regenerative microenvironments. Successful cell therapy depends on many factors, including choice of administration route and application of understanding of cell potency and their therapeutic mechanisms. In this point of view, the authors leverage the tumultuous history of the field to demonstrate the need for clinicians to continually update themselves as new discoveries are made in order to avoid misalignments in the future, especially regarding administration routes and dose frequency, as well as to explore recent insights into MSC plasticity, therapeutic mechanisms, and cell delivery systems.     

Precise tissue bioengineering and niches of mesenchymal stem cells: Their size and hierarchy matter

Stem cell microterritories (niches), as a specialized part of the extracellular matrix (ECM), are considered an important target and tool for the development of new materials, medical implants, and devices. However, tissue bioengineering products that have stem cell niches of known size on the surface or in the bulk structure of artificial materials are practically unknown. This brief review attempts to draw attention to the problematic aspects of niches as specific parts of the ECM, such as their hierarchy and size for mesenchymal stromal/stem cells (MSCs). These parameters arise directly from numerous definitions of stem cell niches as specialized morphological microterritories found in various tissues. The authors of this review analyze the known information on the hierarchy of MSC microterritories by analogy with that of hematopoietic stem cells. Occasional reports on the size of artificial MSC niches compared to natural niche candidates are summarized. A consensus on a hierarchy and optimal range of niche sizes for MSCs and other stem cells is needed to accelerate the development of prototyping technologies and additive manufacturing in applications to precise tissue bioengineering and regenerative medicine.     

Tuning mesenchymal stem cell secretome therapeutic potential through mechanotransduction

Mesenchymal stem cells (MSCs) and their byproducts have been widely validated as potential therapeutic products for regenerative medicine. The therapeutic effects result mainly from the paracrine activity of MSCs, which consists of the secretion of bioactive molecules, whether dispersed in medium conditioned by cell culture or encapsulated in extracellular vesicles. The composition of the MSC secretome, which represents the set of these secreted cellular products, is crucial for the performance of the desired therapeutic functions. Different cell culture strategies have been employed to adjust the secretome composition of MSCs to obtain the best therapeutic responses for different clinical contexts. However, the manipulation of culture conditions has focused mainly on the use of different biochemical elements for the preconditioning of MSCs and less on the physical conditions of the cell culture environment. Herein, we offer our point of view regarding the importance of the physical properties of cell culture substrates and their mechanotransduction responses in preconditioning the MSCs secretome. We highlight the relevance of studying mechanotransduction events associating cell morphology and the modulation of gene expression to customize and expand the use of MSCs secretomes.     

The antioxidant trolox inhibits aging and enhances prostaglandin E-2 secretion in mesenchymal stem cells

Mesenchymal stem cells (MSCs) have been widely used in regenerative medicine and clinical therapy due to their capabilities of proliferation, differentiation, and immune regulation. However, during in vitro expansion, MSCs are prone to aging, which largely limits their application. Prostaglandin E-2 (PGE-2) is a key effector secreted by MSCs to exert immunomodulatory effects. By screening the compound library for PGE-2 secretion, the antioxidant trolox was verified as a stimulator of MSCs to secrete PGE-2. The effect of antioxidant trolox on biological characteristics of MSCS, including aging, proliferation, and gene expression, was examined. The results demonstrated that trolox can resist aging, promote proliferation, and enhance PGE-2 secretion of MSCs without affecting their surface marker expression. Furthermore, trolox treatment up-regulates miR-17-92 clusters in MSCs and may contribute to its anti-aging effects. Thus, trolox addition might be beneficial for MSCs expansion and their application.     

Dental pulp stem cells and banking of teeth as a lifesaving therapeutic vista

Exfoliated deciduous or an extracted healthy adult tooth can be used to harvest, process, and cryogenically preserve dental pulp stem cells. Future stem cell-based regenerative medicine methods could benefit significantly from these mesenchymal stem cells. Teeth serve as a substantial source of mesenchymal stem cells, otherwise disposed of as medical waste. Care should be taken to store this treasure trove of stem cells. Collective responsibility of patients, dentists, and physicians is necessary to ensure that this valuable resource is not wasted and that every possible dental pulp stem cell is available for use in the future. The dental pulp stem cells (DPSC) inside teeth represent a significant future source of stem cells for regenerative medicine procedures. This review describes the ontogeny, the laboratory processing and collection, and isolation methods of DPSC. This review also discusses currently available stem cell banking facilities and their potential use in regenerative medicine procedures in dental and general medical applications in the future.     

Stem cells in intervertebral disc regeneration–more talk than action?

Pain and lifestyle changes are common consequences of intervertebral disc degeneration (IVDD) and affect a large part of the aging population. The stemness of cells is exploited in the field of regenerative medicine as key to treat degenerative diseases. Transplanted cells however often face delivery and survival challenges, especially in tissues with a naturally harsh microniche environment such as the intervertebral disc. Recent interest in the secretome of stem cells, especially cargo protected from microniche-related decay as frequently present in degenerating tissues, provides new means of rejuvenating ailing cells and tissues. Exosomes, a type of extracellular vesicles with purposeful cargo gained particular interest in conveying stem cell related attributes of rejuvenation, which will be discussed here in the context of IVDD.     

Mesenchymal stem cells-derived extracellular vesicles as ‘natural’ drug delivery system for tissue regeneration

Mesenchymal stem cells (MSCs) have abilities to mediate tissue protection through mechanisms of anti-apoptosis, anti-oxidative stress and anti-fibrosis as well as tissue regeneration through mechanisms of cell proliferation, differentiation and angiogenesis. These effects by MSCs are mediated by a variety of factors, including growth factors, cytokines and extracellular vesicles (EVs). Among these factors, EVs, containing proteins, mRNA and microRNAs (miRNA), may carry their contents into distant tissues with high stability. Therefore, the treatment with MSC-derived EVs may be promising as ‘natural’ drug delivery systems (DDS). Especially, the treatment of MSC-derived EVs with the manipulation of specific miRNAs expression has been reported to be beneficial under a variety of diseases and tissue injuries. The overexpression of specific miRNAs in the EVs might be through pre-loading method using the gene editing system by plasmid vector or post-loading method to load miRNA mimics into EVs by electroporation or calcium chloride-mediated transfection. Despite current several challenges for clinical use, it should open the next era of regenerative medicine for a variety of diseases. In this article, we highlight the therapeutic potential of MSC-derived EVs as ‘natural’ DDS and current challenges.     

分子影像技术活体追踪移植干细胞的研究进展

干细胞具有分化、再生能力,通过体外扩增和体内移植,可以治疗各种组织坏损和退化性疾病(如心脑血管疾病、脑脊髓外伤和糖尿病等),具有极大的应用前景,是目前国际、国内的研究热点。利用核素显像、磁共振成像和光成像等分子影像技术,通过体外直接标记、报告基因或功能显示等追踪策略,可以显示干细胞在活体内的分布和变化,明确其最终归宿和产生的功能。合理选择这些分子影像技术和追踪策略,或通过互补结合,将有助于阐明干细胞在活体内的作用机制和相关的影响因素,指导临床干细胞治疗抉择和疗效评估。     

MSCs-exosomes in regeneration medicine: Current evidence and future perspectives

Exosomes, especially from mesenchymal stem cells, have attracted extensive attention in regeneration medicine. Mesenchymal stem cells derived exosomes (MSCs-exosomes) have shown anti-inflammatory, anti-oxidant, anti-apoptosis and tissue regeneration effects in a variety of tissue injury repair models. MSCs-exosomes hold many excellent properties such as low immunogenicity, biocompatibility, and targeting capability. With the in-depth study on the generation and function of exosomes, MSCs-exosomes are considered to be the bright stars in the field of regenerative medicine. However, there are still many obstacles to overcome in terms of exosomes isolation, clinical trials and safety evaluation. In this article, what we should focus on about MSCs-exosomes in regeneration medicine will be discussed.     

Mesenchymal stem cell-derived exosome: The likely game-changer in stem cell research

Stem cell research is a promising area of transplantation and regenerative medicine with tremendous potential for improving the clinical treatment and diagnostic options across a variety of conditions and enhancing understanding of human development. Over the past few decades, mesenchymal stem cell (MSCs) studies have exponentially increased with a promising outcome. However, regardless of the huge investment and the research attention given to stem cell research, FDA approval for clinical use is still lacking. Amid the challenges confronting stem cell research as a cell-based product, there appears to be evidence of superior effect and heightened potential success in its expressed vesicles, exosomes, as cell-free products. In addition to their highly desirable intrinsic biologically unique structural, compositional, and morphological characteristics, as well as predominant physiochemical stability and biocompatibility properties, exosomes can also be altered to enhance their therapeutic capability or diagnostic imaging potential via physical, chemical, and biological modification approaches. More importantly, the powerful therapeutic potential and superior biological functions of exosomes, particularly, regarding engineered exosomes as cell-free products, and their utilization in a new generation of nanomedicine treatment, vaccination, and diagnosis platforms, brings hope of a change in the near future. This viewpoint discusses the trend of stem cell research and why stem cell-derived exosomes could be the game-changer.     

Dental-derived stem cells and biowaste biomaterials: What’s next in bone regenerative medicine applications

The human teeth and oral cavity harbor various populations of mesenchymal stem cells (MSCs), so called dental-derived stem cells (D-dSCs) with self-renewing and multilineage differentiation capabilities. D-dSCs properties involves a strong paracrine component resulting from the high levels of bioactive molecules they secrete in response to the local microenvironment. Altogether, this viewpoint develops a general picture of current innovative strategies to employ D-dSCs combined with biomaterials and bioactive factors for regenerative medicine purposes, and offers information regarding the available scientific data and possible applications.     

Adipose-derived mesenchymal stem/stromal cells: from the lab bench to the basic concepts for clinical translation

In the last years, much work has shown that the most effective repair system of the body is represented by stem cells, which are defined as undifferentiated precursors that own unlimited or prolonged self-renewal ability, which also have the potential to transform themselves into various cell types through differentiation.All tissues that form the body contain many different types of somatic cells, along with stem cells that are called ‘mesenchymal stem (or stromal) cells’ (MSC). In certain circumstances, some of these MSC migrate to injured tissues to replace dead cells or to undergo differentiation to repair it.The discovery of MSC has been an important step in regenerative medicine because of their high versatility. Moreover, the finding of a method to isolate MSC from adipose tissue, so called ‘adipose-derived mesenchymal stem cells’ (ASC), which share similar differentiation capabilities and isolation yield that is greater than other MSC, and less bioethical concerns compared to embryonic stem cells, have created self-praised publicity to procure almost any treatment with them. Here, we review the current techniques for isolation, culture and differentiation of human ASC (hASC), and describe them in detail. We also compile some advantages of the hASC over other stem cells, and provide some concepts that could help finding strategies to promote their therapeutic efficiency.     

Exosomes from adipose tissue-derived stem/stromal cells: A key to future regenerative medicine

Advances in regenerative medicine correlate strongly with progress in the use of adipose tissue-derived mesenchymal stem/stromal cells. The range of therapeutic indications has also expanded over recent years. Numerous recent studies have highlighted the primary importance of paracrine secretion by these cells. Though it is interesting to compare the different types of such secretions, we believe that exosomes (extra-cellular vesicles possessing the same properties as their source cells) will likely be the main key in tomorrow’s cell therapy. Exosomes also have many advantages compared to the direct use of cells, making these particles a major target in fundamental and translational research.     

Mesenchymal stem cell-derived exosomes as new remedy for the treatment of inflammatory eye diseases

Detrimental immune response has a crucially important role in the development and progression of inflammatory eye diseases. Inflammatory mediators and proteolytic enzymes released by activated immune cells induce serious injury of corneal epithelial cells and retinal ganglion cell which may result in the vision loss. Mesenchymal stem cells (MSCs) are regulatory cells which produce various immunosuppressive factors that modulate phenotype and function of inflammatory immune cells. However, several safety issues, including undesired differentiation and emboli formation, limit clinical use of MSCs. MSC-derived exosomes (MSC-Exos) are nano-sized extracellular vesicles which contain all MSC-derived immunoregulatory factors. Intraocular administration of MSC-Exos efficiently attenuated eye inflammation and significantly improved visual acuity in experimental animals without causing any severe side effects. As cell-free product, MSC-Exos addressed all safety issues related to the transplantation of MSCs. Therefore, MSC-Exos could be considered as potentially new remedy for the treatment of inflammatory eye diseases which efficacy should be explored in up-coming clinical trials.