Current Stem Cell Research & Therapy

Several approaches have been adopted to study cancer stem cells from several tissues including solid tumors. To study cancer stem cells, there are some basic concepts of stem cells biology that researchers have to considerer, for example “selfrenewal capacity” [1, 2], however, some scientists take this functional characteristic for granted in their experiments obviating the main feature of stem cells. In this issue, we provided an overview of several topics of cancer stem cells from solid tumors, and how researchers have been studying them. In general, surface proteins have been used to identify and isolate cancer stem cells from several tissues. Moreover, it is interesting to discuss the role of CD24 [3], CD44 [4], CD49 [5], Lgr5 [6], CD133 [7] and others proteins that have been used as common stem cell markers. Most of these cancer stem cell markers have a relevant influence to maintain the stemness of cancer stem cells, such as ALDH, an enzyme that is involved in aldehydes-derived drug resistance, nevertheless ALDH also has a role to maintain stemness [8] by an unknown mechanism. So far, cancer stem cells study requires knowing exactly how these cells work, considering their phenotype and their basic functional roles in tumor growth. Also, microenvironment and cellular niche influence the cancer stem cells behavior by cell signaling pathways including cell adhesion molecule interactions such as CD49, an integrin that interacts with tumor microenvironment ligands promoting cell moving, migration and also metastasis [9]. Likewise, the role of sex hormones in Hormone-regulated tumors, like breast cancer has been poorly studied and the results are still controversial, due to in part, by the difference in sex hormone concentration tested, estrogen and progesterone receptor expression, as well as the experimental models that have been used [10]. Further, some authors reviewed the relevant function of cancer stem cells in metastatic disease. Finally, a targeted approach is also used in cancer stem cell field by pointing out the self-renewal and drug resistance mechanisms to eliminate these high tumorigenic cells [11]. In summary, this thematic issue can give to the reader a critic overview about cancer stem cells in some solid tumors.

Unrevealed biology, apart from the difficult nomenclature [1], places progenitor cells of mesodermal tissues, mesenchymal stem cells – “MSC” in the focus of stem cell debate. Although cell compartments in many adult tissues have stem cell potential, it seems that “MSC” are not ubiquitous populations, requiring a refinement of “MSC” concept. It follows from this that we are still not able to wholly define the nature of primary niche and “MSC” response to homeostatic or stress signals. Even the most important, per se “MSC” features, which should clearly separate them from other cell populations in certain tissue and reveal whether and how “MSC” possess mechanisms to keep their stem cell autonomy (if exists) [2] apart from microenvironmental factors, are still not clarified. Thus, it is paramount to keep on working to deconvolute the molecular, cellular and spatial composition of primary “MSC” niche, stemness and lineage restriction. This Special Issue brings several manuscripts describing “MSC” in the context of their identification and in vitro evaluated properties which could be clinically important. The manuscripts addressed several topics: developmental position and phenotype, immunomodulatory properties and engineering strategies designed to upscale differentiation capacity of “MSC”. Elucidation of “MSC” phenotype is difficult due to overlapping markers for different cell populations and non-existing indispensable correlation of these markers and stem cell potential, where the Authors thoroughly described position of “MSC” in bone marrow, referring to skeletal stem cells [3] and highly remodeling tissue of endometrium, considering “MSC” as rare cells [4]. Poggi & Zocchi [5] critically reviewed immunomodulatory functions of “MSC”, pointing the questionable perception of in vitro propagated “MSC” features, where cultured population contains low frequency of real stem cells. Aware of different flaws following “MSC“ in vitro assay, researchers pragmatically attempt to find functions of “MSC” with potential clinical relevance. Immunomodulatory activities as well as (pre)clinical utility of “MSC” reported in amniotic fluid were described [6]. Engineering strategies, including manipulation of “MSC” microenvironment, were found to be an important approach for dental [7], bone and cartilage tissues reconstruction (Mesure et al.). Indeed, results obtained in in vivo studies, only if rigorously interpreted, may help to perceive whether observed effects have anything in common with the primary “MSC” features and activities.

Stem cells interpret signals from their microenvironment while simultaneously modifying the niche through secreting factors and exerting mechanical forces. Many soluble stem cell cues have been determined over the past century, but in the past decade, our molecular understanding of mechanobiology has advanced to explain how passive and active forces induce similar signaling cascades that drive self-renewal, migration, differentiation or a combination of these outcomes. All these findings directly affected the further molecular understanding of relevant diseases and treatment. Therefore, improvements in understanding of these signaling pathways cascades will greatly improve the knowledge not only in stem cell culture methods, materials and biophysical tools development, but also for improving the knowledge of relevant diseases developing and treatment. Here, we in this special theme issue, we try to organize experts in this fields to summarize recent research findings of signaling pathways involved in stem cell differentiation and relevant therapy, then publish a series of review articles and research papers in order to offer perspective on ongoing challenges. Four reviews included from the experts in the field of medical research and clinical therapeutic practice covering the cutoff point of the stem cell and relevant signaling pathways study on the orthopedics, oncology, neurobiology and ophthalmology. Wang et al. [1] reviewed the progress of genetic tools for specific lineage tracing with emphasis on their applications in investigating the stem cell niche signals. In this review, three most commonly used genetic lineage tracing strategies, namely: one-component, two-component, and three-component genetic tools have been systematically reviewed according to the development of technique, particularly the advantages and disadvantages of individual methods and further focus on their application in the niche signaling studies of stem cell fields. Zhu et al. [2] reviewed the potential of stem cells in the treatment of adult patients with osteonecrosis of femoral head (ONFH). With the rise of interdisciplinary, stem cell therapy combined with platelet-rich plasma therapy, gene therapy or other methods are gradually attracted the attention of researchers. In this review, they summarize the current advances in stem cell therapy for ONFH, as well as the problems and challenges, which may provide a reference for further research. Growing evidence support that NF-κB plays a major role in oncogenesis as well as its well-known function in the regulation of immune responses and inflammation in stem cell study. Therefore, Zhu et al. [3] conducted a review of the diverse molecular mechanisms which the NF-κB pathway is constitutively activated in different types of human cancers and the potential role of various oncogenic genes regulated by this transcription factor in cancer development and progression. They also discussed the spleen tyrosine kinase (Syk) mediates signal transduction downstream of a variety of transmembrane receptors including classical immune-receptors like the B-cell receptor (BCR), which activate the inflammasome and NF-κB-mediated transcription of chemokines and cytokines in presence of pathogens would be discussed as well. The highlight of this review article is to summarize the classic and novel signaling pathways involved NF-κB and Syk signaling and then raise some possibilities for cancer therapy. Bone marrow mesenchymal stem cells (BMSCs), with its capacity for multi-directional differentiation, low immunogenicity and high portability, which made BMSCs serve as ideal “seed cells” in ophthalmological disease therapy. Ma et al. [4] examined recent literature concerning the potential application of BMSCs for the treatment of ophthalmological disease, which includes the activity of transplanted cells, migration and homing of BMSCs, immuno-modulatory and anti-inflammatory effects of BMSCs and signaling involved. Each aspect is complementary to the others and together these aspects promoted further understanding for the potential use of BMSCs in treating ophthalmological diseases. We hope that this thematic issue will be beneficial for the vast readers and may serve as a good source of literature for the scholars in the field of each relevant fields.

During the last few years, tissue engineering has widely propagated forwards like a tidal wave, providing a new concept for the use of stem cells, small molecules and biomaterials. In contrast to classic tissue repair approaches, the newly proposed strategies aim to induce new functional tissues, rather than simply implanting replacement of alloplastic or allogenic parts. This special issue from Current Stem Cell Research & Therapy examines the regeneration of damaged tissues driven by different new strategies using stem cells or small molecules. This special issue also includes articles presenting complex biological processes required to restore functionality of tissue when the regulatory function changes. It invites high-quality review papers describing the design of novel multifunctional therapeutic systems that facilitate tissue regeneration across different tissue types