Current Stem Cell Research & Therapy - Volume 14, Issue 4, 2019

Monthly changes in the endometrial cycle indicate the presence of endometrial stem cells. In recent years, various stem cells that exist in the endometrium have been identified and characterized. Additionally, many studies have shown that Bone Marrow Mesenchymal Stem Cells (BM-MSCs) provide an alternative source for regenerating the endometrium and repairing endometrial injury. This review discusses the origin of endometrial stem cells, the characteristics and main biomarkers among five types of putative endometrial stem cells, applications of endometrium-derived stem cells and menstrual blood-derived stem cells, the association between BM-MSCs and endometrial stem cells, and progress in repairing endometrial injury.

The bone marrow hosts skeletal progenitor cells which have most widely been referred to as Mesenchymal Stem or Stromal Cells (MSCs), a heterogeneous population of adult stem cells possessing the potential for self-renewal and multilineage differentiation. A consensus agreement on minimal criteria has been suggested to define MSCs in vitro, including adhesion to plastic, expression of typical surface markers and the ability to differentiate towards the adipogenic, osteogenic and chondrogenic lineages but they are critically discussed since the differentiation capability of cells could not always be confirmed by stringent assays in vivo. However, these in vitro characteristics have led to the notion that progenitor cell populations, similar to MSCs in bone marrow, reside in various tissues. MSCs are in the focus of numerous (pre)clinical studies on tissue regeneration and repair. Recent advances in terms of genetic animal models enabled a couple of studies targeting skeletal progenitor cells in vivo. Accordingly, different skeletal progenitor cell populations could be identified by the expression of surface markers including nestin and leptin receptor. While there are still issues with the identity of, and the overlap between different cell populations, these studies suggested that specific microenvironments, referred to as niches, host and maintain skeletal progenitor cells in the bone marrow. Dynamic mutual interactions through biological and physical cues between niche constituting cells and niche inhabitants control dormancy, symmetric and asymmetric cell division and lineage commitment. Niche constituting cells, inhabitant cells and their extracellular matrix are subject to influences of aging and disease e.g. via cellular modulators. Protective niches can be hijacked and abused by metastasizing tumor cells, and may even be adapted via mutual education. Here, we summarize the current knowledge on bone marrow skeletal progenitor cell niches in physiology and pathophysiology. We discuss the plasticity and dynamics of bone marrow niches as well as future perspectives of targeting niches for therapeutic strategies.

Mesenchymal stem cells (MSCs) are multipotent stem cells with wide-ranging clinical applications due to their ability to regenerate tissue from mesenchymal origin and their capability of suppressing immune responses, thus reducing the likelihood of graft versus host disease after transplantation. MSCs can be isolated from a variety of sources including bone marrow, adipose tissue, umbilical cord blood, and immature teeth. Dental stem cells (DSCs) possess progenitor and immunomodulatory abilities as the other MSC types and because they can be easily isolated, are considered as attractive therapeutic agents in regenerative dentistry. Recently, it has been shown that DSCs seeded onto newly developed synthetic biomaterial scaffolds have retained their potential for proliferation and at the same time have enhanced capabilities for differentiation and immunosuppression. The scaffolds are becoming more efficient at MSC priming as researchers learn how short peptide sequences alter the adhesive and proliferative capabilities of the scaffolds by stimulating or inhibiting classical osteogenic pathways. New findings on how to modulate the inflammatory microenvironment, which can prime DSCs for differentiation, combined with the use of next generation scaffolds may significantly improve their therapeutic potential. In this review, we summarize current findings regarding DSCs as a potential regenerative therapy, including stem cell priming with inflammatory cytokines, types of scaffolds currently being explored and the modulation of scaffolds to regulate immune response and promote growth.

Background: Amniotic Fluid Derived Mesenchymal Stem Cells (AF-MSCs) are adult, fibroblast- like, self-renewable, multipotent stem cells. During the last decade, the therapeutic potential of AF-MSCs, based on their huge differentiation capacity and immunomodulatory characteristics, has been extensively explored in animal models of degenerative and inflammatory diseases. Objective: In order to describe molecular mechanisms responsible for the therapeutic effects of AFMSCs, we summarized current knowledge about phenotype, differentiation potential and immunosuppressive properties of AF-MSCs. Methods: An extensive literature review was carried out in March 2018 across several databases (MEDLINE, EMBASE, Google Scholar), from 1990 to present. Keywords used in the selection were: “amniotic fluid derived mesenchymal stem cells”, “cell-therapy”, “degenerative diseases”, “inflammatory diseases”, “regeneration”, “immunosuppression”. Studies that emphasized molecular and cellular mechanisms responsible for AF-MSC-based therapy were analyzed in this review. Results: AF-MSCs have huge differentiation and immunosuppressive potential. AF-MSCs are capable of generating cells of mesodermal origin (chondrocytes, osteocytes and adipocytes), neural cells, hepatocytes, alveolar epithelial cells, insulin-producing cells, cardiomyocytes and germ cells. AF-MSCs, in juxtacrine or paracrine manner, regulate proliferation, activation and effector function of immune cells. Due to their huge differentiation capacity and immunosuppressive characteristic, transplantation of AFMSCs showed beneficent effects in animal models of degenerative and inflammatory diseases of nervous, respiratory, urogenital, cardiovascular and gastrointestinal system. Conclusion: Considering the fact that amniotic fluid is obtained through routine prenatal diagnosis, with minimal invasive procedure and without ethical concerns, AF-MSCs represents a valuable source for cell-based therapy of organ-specific or systemic degenerative and inflammatory diseases.

Musculoskeletal pathologies, especially those affecting bones and joints, remain a challenge for regenerative medicine. The main difficulties affecting bone tissue engineering are the size of the defects, the need for blood vessels and the synthesis of appropriate matrix elements in the engineered tissue. Indeed, the cartilage is an avascular tissue and consequently has limited regenerative abilities. Thanks to their self-renewal, plasticity and immunomodulatory properties, mesenchymal stem cells (MSCs) became a central player in tissue engineering, and have already been shown to be able to differentiate towards chondrogenic or osteogenic phenotypes. Whether synthetic (e.g. tricalcium phosphate) or from natural sources (e.g. hyaluronic acid), biomaterials can be shaped to fit into bone and cartilage defects to ensure mechanical resistance and may also be designed to control cell spatial distribution or differentiation. Soluble factors are classically used to promote cell differentiation and to stimulate extracellular matrix synthesis to achieve the desired tissue production. But as they have a limited lifetime, transfection using plasmid DNA or transduction via a viral vector of therapeutic genes to induce the cell secretion of these factors allows to have more lasting effects. Also, the chondrocyte phenotype may be difficult to control over time, with for example the production of hypertrophic or osteogenic markers that is undesirable in hyaline cartilage. Thus, tissue regeneration strategies became more elaborate, with an attempt at associating the benefits of MSCs, biomaterials, and gene therapy to achieve a proper tissue repair. This minireview focuses on in vitro and in vivo studies combining biomaterials and gene therapy associated with MSCs for bone and cartilage engineering.

Mesenchymal stromal cells (MSC) are mesodermal elements characterized by the ability to differentiate into several types of cells present mainly in connective tissues. They play a key function in tissue homeostasis and repair. Furthermore, they exert a strong effect on both innate and adaptive immune response. The main current of thought considers MSC as strong inhibitors of the immune system. Indeed, the first description of MSC immunomodulation pointed out their inability to induce alloimmune responses and their veto effects on mixed lymphocyte reactions. This inhibition appears to be mediated both by direct MSC interaction with immune cells and by soluble factors. Unfortunately, evidence to support this notion comes almost exclusively from in vitro experiments. In complex experimental systems, it has been shown that MSC can exert immunosuppressive effects also in vivo, either in murine models or in transplanted patients to avoid the graft versus host disease. However, it is still debated how the small number of administered MSC can regulate efficiently a large number of host effector lymphocytes. In addition, some reports in the literature indicate that MSC can trigger rather than inhibit lymphocyte activation when a very low number of MSC are co-cultured with lymphocytes. This would imply that the ratio between the number of MSC and immune cells is a key point to forecast whether MSC will inhibit or activate the immune system. Herein, we discuss the conflicting results reported on the immunomodulatory effects of MSC to define which features are relevant to understand their behavior and cross-talk with immune cells.

Objectives: A variety of bioreactors and related approaches have been applied to dental tissues as their use has become more essential in the field of regenerative dentistry and dental tissue engineering. The review discusses the various types of bioreactors and their potential application in dentistry. Methods: Review of the literature was conducted using keywords (and MeSH) like Bioreactor, Regenerative Dentistry, Fourth Factor, Stem Cells, etc., from the journals published in English. All the searched abstracts, published in indexed journals were read and reviewed to further refine the list of included articles. Based on the relevance of abstracts pertaining to the manuscript, full-text articles were assessed. Results: Bioreactors provide a prerequisite platform to create, test, and validate the biomaterials and techniques proposed for dental tissue regeneration. Flow perfusion, rotational, spinner-flask, strain and customize-combined bioreactors have been applied for the regeneration of bone, periodontal ligament, gingiva, cementum, oral mucosa, temporomandibular joint and vascular tissues. Customized bioreactors can support cellular/biofilm growth as well as apply cyclic loading. Center of disease control & dip-flow biofilm-reactors and micro-bioreactor have been used to evaluate the biological properties of dental biomaterials, their performance assessment and interaction with biofilms. Few case reports have also applied the concept of in vivo bioreactor for the repair of musculoskeletal defects and used customdesigned bioreactor (Aastrom) to repair the defects of cleft-palate. Conclusions: Bioreactors provide a sterile simulated environment to support cellular differentiation for oro-dental regenerative applications. Also, bioreactors like, customized bioreactors for cyclic loading, biofilm reactors (CDC & drip-flow), and micro-bioreactor, can assess biological responses of dental biomaterials by simultaneously supporting cellular or biofilm growth and application of cyclic stresses.

Cord Blood (CB) is a unique and readily available source of hematopoietic stem cells for transplantation. CB also contains other types of stem cells, including endothelial stem cells and mesenchymal stem cells, that may prove useful in non-traditional clinical uses. Genetic and molecular analyses have demonstrated that CB stem cells lie somewhere between mature stem cells like those found in Bone Marrow (BM), and fetal stem cells. After 25 years of clinical experience, CB is now used in the same fashion as BM for all typical malignant and genetic diseases treated by bone marrow transplant. Due to the establishment of CB banks in the US and abroad, more than 35,000 CB transplants have been performed over the past 25 years. An average of 700-800 CB transplants are performed annually. In addition, CB is now used more frequently for regenerative medicine and tissue engineering applications. At first glance, it seems that everything could not be better with the public cord blood banks and the use of their samples in the clinic. However, a recent report by the Rand Corp. reviewed the US national cord blood stem cell banking program and detailed many ongoing problems. However, some details were omitted from the report that would shed some light on the causes of many of the problems. This paper will summarize the status of the public cord blood stem cell banking program in the US, detail the problems associated with the program that could jeopardize its existence and suggest possible solutions to resolve these issues.