Cell-derived extracellular vesicles and membranes for tissue repair

Humans have a limited postinjury regenerative ability. Therefore, cell-derived biomaterials have long been utilized for tissue repair. Cells with multipotent differentiation potential, such as stem cells, have been administered to patients for the treatment of various diseases. Researchers expected that these cells would mediate tissue repair and regeneration through their multipotency. However, increasing evidence has suggested that in most stem cell therapies, the paracrine effect but not cell differentiation or regeneration is the major driving force of tissue repair. Additionally, ethical and safety problems have limited the application of stem cell therapies. Therefore, nonliving cell-derived techniques such as extracellular vesicle (EV) therapy and cell membrane-based therapy to fulfil the unmet demand for tissue repair are important. Nonliving cell-derived biomaterials are safer and more controllable, and their efficacy is easier to enhance through bioengineering approaches. Here, we described the development and evolution from cell therapy to EV therapy and cell membrane-based therapy for tissue repair. Furthermore, the latest advances in nonliving cell-derived therapies empowered by advanced engineering techniques are emphatically reviewed, and their potential and challenges in the future are discussed. Graphical Abstract

Characteristics of Mesenchymal Stem Cells Are Independent of Bone Marrow Storage Temperatures

Mesenchymal stem cells play an important role in regenerative medicine due to their capability of self-renewal and multipotent differentiation. For research or clinical application, bone marrow aspirates are harvested during elective surgeries to isolate MSCs. If an immediate purification of the MSCs is not possible, the bone marrow must be stored. Therefore, the aim of this study was to investigate possible differences of stem cell characteristics regarding the self-renewal capability, the adipogenic, chondrogenic, and osteogenic differentiation, and the expression of surface antigens after different storage conditions of the bone marrow aspirates. Three groups were analysed: the first group was purified immediately after harvesting, the other two groups were processed after they were stored 18 to 24 hours at 22°C (room temperature) or at 4°C. Comparisons between the groups were performed using the Kruskal-Wallis test for nonparametric data. The final results showed no significant difference between the different storage conditions. Therefore, storage of bone marrow aspirates for 18 to 24 hours at room temperature or 4°C is possible without loss of stem cell characteristics.

Cell and Cell-Free Therapies to Counteract Human Premature and Physiological Aging: MSCs Come to Light

The progressive loss of the regenerative potential of tissues is one of the most obvious consequences of aging, driven by altered intercellular communication, cell senescence and niche-specific stem cell exhaustion, among other drivers. Mesenchymal tissues, such as bone, cartilage and fat, which originate from mesenchymal stem cell (MSC) differentiation, are especially affected by aging. Senescent MSCs show limited proliferative capacity and impairment in key defining features: their multipotent differentiation and secretory abilities, leading to diminished function and deleterious consequences for tissue homeostasis. In the past few years, several interventions to improve human healthspan by counteracting the cellular and molecular consequences of aging have moved closer to the clinic. Taking into account the MSC exhaustion occurring in aging, advanced therapies based on the potential use of young allogeneic MSCs and derivatives, such as extracellular vesicles (EVs), are gaining attention. Based on encouraging pre-clinical and clinical data, this review assesses the strong potential of MSC-based (cell and cell-free) therapies to counteract age-related consequences in both physiological and premature aging scenarios. We also discuss the mechanisms of action of these therapies and the possibility of enhancing their clinical potential by exposing MSCs to niche-relevant signals.

Autophagy and Metabolism in Normal and Malignant Hematopoiesis

The hematopoietic system relies on regulation of both metabolism and autophagy to maintain its homeostasis, ensuring the self-renewal and multipotent differentiation potential of hematopoietic stem cells (HSCs). HSCs display a distinct metabolic profile from that of their differentiated progeny, while metabolic rewiring from glycolysis to oxidative phosphorylation (OXPHOS) has been shown to be crucial for effective hematopoietic differentiation. Autophagy-mediated regulation of metabolism modulates the distinct characteristics of quiescent and differentiating hematopoietic cells. In particular, mitophagy determines the cellular mitochondrial content, thus modifying the level of OXPHOS at the different differentiation stages of hematopoietic cells, while, at the same time, it ensures the building blocks and energy for differentiation. Aberrations in both the metabolic status and regulation of the autophagic machinery are implicated in the development of hematologic malignancies, especially in leukemogenesis. In this review, we aim to investigate the role of metabolism and autophagy, as well as their interconnections, in normal and malignant hematopoiesis.

Mesenchymal stem cell- mediated immunomodulation and the potential therapeutic application in Crohn’s Disease

Mesenchymal stem cells (MSCs) are self-renewing stromal cells that possess a multipotent differentiation capacity as they can differentiate into numerous cell types such as adipose, bone and cartilage cells. MSCs have generated considerable interest for their remarkable tissue-reparative and immunomodulatory properties whereby MSCs can develop into functional cells at the injury site and control the body’s response to tissue damage respectively. Consequently, MSCs have vast therapeutic potential in treating Crohn’s disease (CD) which is a lifelong inflammatory bowel disease where tissue damage to a section of the gastrointestinaltract occurs. The review aims to discuss the properties of MSCs and explore their potential application in treating CD. This review highlights the tissue-reparative properties of MSCs and specifically focuses on the immunomodulatory properties of MSCs. Results from clinical trials regarding the efficacy and safety of MSCs have been promising, proving that MSCs could potentially be used to treat CD.

Importance of In Vitro Microenvironment on Differentiation and Translational Applications of Dental Pulp Stem Cells

Dental Pulp Stem Cells (DPSCs) are adult stem cells found in dental pulp tissue, and possess the capacity for self-renewal and the potential for multipotent differentiation. DPSCs depend on regulating in vitro microenvironment, and can readily differentiate into osteoblasts, odontoblasts, neurocytes, adipocytes, chondrocytes, myocytes, fibrocytes and many others. In addition, DPSCs play a crucial role in tooth regeneration, bone and nerve repair in current studies of regenerative medicine and tissue engineering. Among them, the influences of stem cell microenvironment or niche on the biological activity of DPSCs are critical and hamper its progress. Herein, we review the influence of culture condition, tissue source, growth factor requirements, and cellular organizational scaffolds and how these features influence the biological characteristics and translational research of DPSCs.

CD73+ Mesenchymal Stem Cells Ameliorate Myocardial Infarction by Promoting Angiogenesis

With multipotent differentiation potential and paracrine capacity, mesenchymal stem cells (MSCs) have been widely applied in clinical practice for the treatment of ischemic heart disease. MSCs are a heterogeneous population and the specific population of MSCs may exhibit a selective ability for tissue repair. The aim of our research was to adapt the CD73+ subgroup of adipose derived MSCs (AD-MSCs) for the therapy of myocardial infarction (MI). In this research, AD-MSCs were isolated from adipose tissue surrounding the groin of mice and CD73+ AD-MSCs were sorted using flow cytometry. To investigate the therapeutic effects of CD73+ AD-MSCs, 1.2 × 106 CD73+ AD-MSCs were transplanted into rat model of MI, and CD73– AD-MSCs, normal AD-MSCs transplantation served as control. Our results revealed that CD73+ AD-MSCs played a more effective role in the acceleration function of cardiac recovery by promoting angiogenesis in a rat model of MI compared with mixed AD-MSCs and CD73– AD-MSCs. Moreover, with the expression of CD73 in AD-MSCs, the secretion of VEGF, SDF-1α, and HGF factors could be promoted. It also shows differences between CD73+ and CD73– AD-MSCs when the transcription profiles of these two subgroups were compared, especially in VEGF pathway. These findings raise an attractive outlook on CD73+ AD-MSCs as a dominant subgroup for treating MI-induced myocardial injury. CD73, a surface marker, can be used as a MSCs cell quality control for the recovery of MI by accelerating angiogenesis.

Key Markers and Epigenetic Modifications of Dental-Derived Mesenchymal Stromal Cells

As a novel research hotspot in tissue regeneration, dental-derived mesenchymal stromal cells (MSCs) are famous for their accessibility, multipotent differentiation ability, and high proliferation. However, cellular heterogeneity is a major obstacle to the clinical application of dental-derived MSCs. Here, we reviewed the heterogeneity of dental-derived MSCs firstly and then discussed the key markers and epigenetic modifications related to the proliferation, differentiation, immunomodulation, and aging of dental-derived MSCs. These messages help to control the composition and function of dental-derived MSCs and thus accelerate the translation of cell therapy into clinical practice.

Stromal Vascular Fraction: Biology and Application Outlook

Stromal vascular fraction (SVF) is a heterogeneous cell extract obtained with enzymatic dissociation of adipose tissue followed by centrifugation. This population includes many different cell types, i.a. adipose tissue stem cells (ATSCs), vascular endothelial and smooth muscle cells and their precursors, pericytes, fibroblasts, macrophages, T-lymphocytes, etc., excluding mature adipocytes. The main SVF component is ATSCs capable of self-renewal and multipotent differentiation. Since early research on SVF, an extensive effort has been aimed at understanding its clinical applications promoting a significant progress in the SVF use for treatment of various diseases and injuries. The past decade has witnessed an upward publication trend in basic and clinical research into the SVF therapeutic value. Manifold methods and devices for the SVF isolation from human liposuction lipoaspirate have been developed, continuously contributing to preclinical and clinical trials of its safety and efficacy. This review discusses the main properties and functions of the SVF cell population, its efficacy and safety for human therapy.