Current Stem Cell Research & Therapy

Cardiac regenerative medicine for heart failure has become a consolidated research field in the past 20 years. Despite the time and effort put by the scientific community into a deeper understanding of the regenerative potential of the heart and its mechanisms, healing an injured heart is still an open challenge. Cell therapy has played an important role in the progression of cardiac regenerative medicine, although many other areas have significantly pushed the field forward, mostly related to cell reprogramming and cell cycle re-entry strategies. Different cardiac and non-cardiac cell populations endowed with specific regenerative/ therapeutic potential have been characterized, and the biological mechanisms responsible for the observed beneficial effects are being studied in both preclinical and clinical settings. The present collection of review articles explores several topics, which can significantly affect the way cardiac regenerative medicine - including cardiac cell therapy - will follow its future steps, and possibly advance towards an increase of its therapeutic benefit. The very initial expectation in the field of cell therapy was a quite straightforward prevision: transplanted undifferentiated cells with cardiogenic potential would replenish the pool of cardiomyocytes lost after an injury by direct differentiation. This expected easy picture has been gradually overcome in favor of a more complex one, involving the interplay between cell populations, a-cellular factors, and the cardiac microenvironment as a whole. With this view, also the development of finely designed biotechnological and bioengineering strategies and tools, needs its own space. Besides transplantation of regenerative progenitors from many sources, strategies of direct in situ reprogramming of resident cells to an undifferentiated state have been progressively explored [1]. This approach gives the double advantage of exploiting the abundance of stromal cells in the heart, while targeting a population contributing to damage and fibrosis, which is fibroblasts. In line with a vision of cell therapy devoid of direct involvement of exogenous cell sources in new tissue generation, many recent and current research studies are investigating indirect paracrine mechanisms of intervention on the damaged myocardium. These mainly include preserving cell viability and function of stressed myocytes, sustaining angiogenesis, counteracting detrimental activation of fibrosis and adverse remodeling, and activating endogenous repair. Indeed, the more potent the beneficial paracrine effect, either through enhanced cell engraftment or paracrine signals potentiation, the more effective the improvement in cardiac function observed in preclinical studies [2]. As anticipated, tissue repair and regeneration involve balance and crosstalk amongst many players and pathways. Thus, cardiac regenerative medicine requires continuous insight into endogenous biological and pathogenetic mechanisms. Myocardial injury is associated, together with other factors, with deranged protein homeostasis and mitochondrial dysfunction, both significantly contributing to cell senescence [3]. This phenomenon involves not only parenchymal cells, but also many other cell types that can mediate impairment or reduction of reparative capacity, such as pericytes, stromal cells, and epicardial cells. The latter, in particular, are significantly involved in cardiac development and repair (once activated) for their paracrine communication with the myocardium [4]. However, the equilibrium between pro-regenerative and pro-fibrotic signaling still requires clarification. An important topic involved in the cardiac muscle repair scenario is intra- and inter-cellular signaling mediated by noncoding RNAs (ncRNAs). They are regulators of cardiac muscle development and homeostasis, with altered ncRNA expression reported to affect the physiology of all different cardiac cell types, including cardiomyocytes and stromal cells [5]. Importantly, both short and long ncRNA can be secreted either as free molecules or transported by extracellular vesicles, and act as mediators of paracrine signaling in cardiac regenerative medicine applications. Cell-free approaches represent a promising frontier, and the strategy seems fully supported by the accredited paracrine hypothesis for therapeutic cell action. Exosomes represent a class of vesicles recently explored as cell products for cardiac regeneration, collected through the secretome of specific reparative cell types, or artificially loaded with desired molecules. Use of acellular products, retaining nonetheless potent biological activity, may overcome several limitations intrinsic to cell therapy, such as immunological concerns, and may allow standardized production. Similarly, another carrier system holding great promise is biomimetic nanoparticles that fuse biological and fabricated components to improve therapeutic efficiency, tissue targeting, and allow controlled release of their content [6]. A lot has been done for understanding what is needed to fix the damaged cardiac muscle, to prevent or, at least, limit its deterioration after injury, but one of the major challenges in cardiac repair still remains the identification of the most effective advanced therapeutic product. Whether cell-based or a-cellular, delivered through injection, cardiac patches or within matrix cocoons, cellular and/or biotechnological therapies seem highly promising options for treating heart failure. A strong interdisciplinary drive, involving cellular and molecular biology, bioengineering, and biomaterials, is already pushing some of these strategies, either alone or in combination, towards rapid clinical translation [7]. The complexity of the regenerative therapy approach currently stimulates challenging experimental settings, as well as the exploration of fields such as nanotechnology. This opens new and exciting perspectives in the design of novel efficient and feasible therapeutic options for treating heart failure patients in the near future.

Macrophages possess stem cell-like abilities for consistent, self-renewal in situ. Heterogeneity, as one of the main hallmarks of macrophages, grant macrophages could perform their biological functions according to various tissue microenvironments, such as: microglia and osteoclasts, in the Central Nervous System (CNS) and bone, respectively. Commonly, macrophages have been classified as M1 macrophages and M2 macrophages, mainly depend on their cellular phenotypes and functional role in immune regulation. To further explain, M1 cells generally function as pro-inflammatory macrophages, whereas M2 cells function as anti-inflammatory macrophages. This is due to the fact that M1 mainly releases inflammatory chemokines and cytokines, including: Reactive Oxygen Intermediate (ROI), Tumor Necrosis Factor-α (TNF-α), and Reactive Nitrogen Intermediate (RNI), whereas its counterpart M2 participates in mitigating inflammation, remodeling and repairing damaged tissue. Therefore, improvements in understanding of macrophages and their cellular properties will greatly improve understanding of inflammatory disease development and treatment. Herein, in our current special issue, we collected works from experts in relevant fields for summarizing their novel findings of macrophages cellular study. Finally, eight review articles were included in our current special issue. These reviews covered the topic range from cellular research to clinical therapeutic practice. Chang et al., [1] reviewed the research progress of active natural products derived from traditional herbal plants (including flavonoids, terpenoids, glycosides, lignans, coumarins, alkaloids) for their role in regulating macrophages, especially in macrophages M2 status polarization. Besides that, in this review, the authors further concluded the possible cellular regulating mechanisms of each compound for their M2 macrophages polarization. This review provides extra details about the therapeutic potential of natural compounds aiming at M2 macrophages polarization. RAW264.7 cell, as a special macrophage cell linage, has been widely used in various studies such as: in vitro induction of osteoclasts and inflammatory cellular model establishment. However, the differentiation process are commonly unstable. The reason might partly be that osteoclasts derived from RAW264.7 are affected by various signaling pathways, such as NF-κB, MAPK, Akt and others. Gao et al., [2] summarized the novel studies for the most recent understanding of the mechanisms underlying the osteoclast formation from RAW264.7. Besides that, the authors also providing additional information about the plant-derived compounds that exert blocking effect on the progression of RAW264.7 for its osteoclastic differentiation via signaling pathways. As two critical substrates of phospholipase Cγ (PLCγ) family, PLCγ1 and PLCγ2 play a crucial role in immune reactions. Liu et al., [3] concluded the role of PLCγ1 and PLCγ2 in regulating the bone marrow macrophages. Besides that, authors also reviewed the role of various natural agents in inhibiting the RANKL signal pathways induced PLCγ activation during osteoclastogenesis from bone marrow macrophages. Although Renal Cell Carcinoma (RCC) is a commonly occurring urologic neoplasm, its pathogenesis remains unknown. Novel studies have demonstrated that macrophages could affect the biological behavior of the RCC. Therefore, Zhang et al., [4] reviewed novel studies on macrophages for their role in the RCC invasiveness and progression. Besides that, the authors also discussed the most recent research on macrophage in RCC for enhancing angiogenesis by regulating tumor microenvironment. Osteoarthritis (OA), as one of the most common degenerative orthopedic diseases, with multiple pathologic changes in joints, affect large populations worldwide. Exosomes derived from mesenchymal cells (include:monocyte/ macrophages) have been given more attention in preventing the OA. Ke et al., [5], in their current review, extensively overviewed the recent advances and challenges related to the role of exosomes in treating OA. Studies demonstrated that mitochondria play a crucial role in the regulation of macrophages polarization. Therefore, Ji et al., [6] extensively explored recent cellular studies about the relationship between the mitochondria and the MSC differentiation. This review provides a further understanding of current cellular culturing protocols, which provides more evidence for facilitating tissue engineering. Simvastatin, lovastatin, rosuvastatin, pravastatin and cerivastatin belong to the statin family, which are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A. Besides that, studies showed that statins exert extensive bioactivities in various cellular environments , such as: anti-inflammatory activity. Interestingly, recent studies have found that these biological activities of stains might be obtained by the regulation of the expression of Cell Adhesion Molecules (CAMs), especially, targeting Lymphocytes Function-Associated Molecules (LFA)-1 and macrophage (Mac)-1. Herein, Meng et al., [7] discussed the regulatory effect of statins on macrophages relevant adhesion factors in different diseases. As the fourth most commonly occurring cancer, Gastric Cancer (GC) was estimated to lead 1.034 million new cases in 2015. Meanwhile, GC as the third-highest mortality cancer, led 785,558 deaths in 2014. A study demonstrated that RhoA could regulate various cellular biological functions, such as: cell adhesion, motor-myosin, cell transformation, and cell migration. Notably, these cellular functions of macrophages are closely related to the immune disorders and tumor cells invasion. Herein, Liu et al., [8] briefly summarized the role of RhoA in inflammatory diseases of immune disorders, as well as biological regulation of tumor cells. Especially, authors reviewed RhoA and its relevant signaling cascades, which are mainly involved in the GC progression.

Stem cell-based tissue engineering is an ever evolving method that holds promise in treating numerous diseases and injuries. It is paramount to precisely regulate the behavior of stem cell such as adhesion, proliferation, migration and differentiation. As the microenvironment in which the stem cells reside plays a remarkable role in regulating cellular behavior [1], providing the suitable stimulatory conditions which can bring about efficient cell promoting microenvironment in vitro and in vivo is one of the ultimate goals for tissue regeneration [2]. Previous research findings [3, 4] showed that adhesion, phenotype and differentiation of stem cells are highly sensitive to the intrinsic physical properties of their microenvironment (such as substrate stiffness, topography). Extrinsic physical stimulation such as strain, stress, compression and vibration are also important for regulating the differentiation of stem cells [5-7]. In addition, the non-contact-dependent methods such as electrical stimulation, electromagnetic field, low-intensity pulsed ultrasound (LIPUS) and laser can affect stem cell behaviors, and effectively enhance the recovery of injured peripheral nerve, bone, tendon, ligament, etc [8-11]. Physical cues are required for generation of functional cell and tissue constructs, by which mechanical stress activates mechano-sensitive receptors, initiates biochemical pathways that lead to the production of mature and functional tissue [2]. Further studies are required with the aim of elucidating the detailed molecular mechanisms involved in the mechanosensitive response of stem cells to various types of physical stimulation. Based on this, employing suitable physical factors that mimic the dynamics of the in vivo microenvironment will provide insights into stem cell-based therapies and tissue engineering. The special issue presented a deep view of the research progress in application of physical stimulation in stem cell-based tissue engineering. Baskan et al. [12] summarize the effects of low-intensity vibration on the stem and progenitor cell populations, including bone marrow-derived stem cells, adipose-derived stem cells, embryonic stem cells, progenitor cells and human periodontal ligament cells. The mechanical signals involved in this process are further discussed. Khorsandi et al. [13] summarize that the photobiomodulation therapy initiates cell proliferation by the increased production of reactive oxygen species, nitric oxide, adenosine triphosphate, and cyclic adenosine monophosphate. In a review article entitled ‘Impact of ultrasound therapy on stem cell differentiation, a systemic review’ by Amini et al. [14], the impact of LIPUS on the differentiation of various stem cells is described, and the frequency, intensity, duration, exposure time of LIPUS are compared based on the references. Arora et al. [15] review the recent advancements in the application of fluid shear stress (SS) in regulating of the differentiation of mesenchymal stem cells (MSCs) into osteogenic, cardiovascular, chondrogenic, adipogenic and neurogenic lineages. They also highlight the importance of combinatorial stimuli for MSCs differentiation which incorporate SS with other mechanical or biochemical stimulus. The paper of Li et al. [16] summarizes the preparation methods of magnetic responsive material (MRM) and comprehensively reports the main applications of MRM in bone tissue engineering. The possible mechanism of MRM in promoting bone repair is also discussed. Heng et al. [17] focus on the use of electrical stimulation to modulate stem cell functions. In another paper, Zhang et al. [18] provide an overview of the effects of stiffness on cell differentiation of bone marrow-derived stem cells, adipose-derived stem cells and neural stem cells. Integrin relevant signaling molecules, including caveolin, piezo and YES-associated protein are also introduced. These cutting-edge reviews highlight the progress in the application of physical stimulation in stem cell-based tissue engineering. As the guest editor of this special issue of Current Stem Cell Research and Therapy, I hope that these papers will provide valuable information on physical stimulation to improve the repair efficiency in tissue engineering.

Bone homeostasis is tightly regulated by bone stem cells (monocyte-macrophage lineage cells of hematopoietic origin), which is the bone-resorbing activity of osteoclasts and bone-forming activity of osteoblasts. Plant-derived compounds medicine has a long history and are widely used in traditional clinical practice to treat bone disease aimed to regulate above two cells. These traditional medical treating methods are characterized by better cost-effectiveness and less side effects to commercial pharmaceutical products. Although a number of plant-derived agents have been reported possess potential effects in treating bone diseases, still, we facing a long way to go for clarifying the therapeutic efficacies of each compound and relevant molecular mechanisms, underlying especially bone stem cells. Six reviews from experts in the field of medical research and clinical therapeutic practice, covering the front edge of the bone homeostasis and studies about naturally occurring compounds, included in the current thematic issue. Zhao et al., [1] reviewed the effects of histone deacetylases (HDAC) inhibitors on the differentiation of stem cells in bone damage repairing and regeneration. In this review, authors mainly focused on the usage and achievements of the deacetylase inhibitors in stem cell differentiation studies and their prospects in repair of bone tissue defects, which offered a good reference to promote stem cell therapy in clinical application. Yang et al., [2] provided a systematic review and meta-analysis of the therapeutic role of puerarin in preventing ovariectomy (OVX)-induced murine postmenopausal osteoporosis model. In this review, authors adopted the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool for animal study methodological quality assessment. Cao et al., [3] reviewed the compound, piceatannol, for its biological activities in various diseases included muscular skeleton disorders. Besides that, authors also reviewed the relevant cellular regulating mechanisms and cellular signaling cascades. Wang et al., [4] reviewed an active agent, triptolide for its specific role in treating osteolysis and other common diseases, such as cancer and cardiovascular disease. Besides that authors further conducted an analysis of the toxicity of this agent and further study speculations. Zhang et al., [5] reviewed studies for the biological functions of myricitrin and its anti-inflammatory role in bone loss. Wen et al., [6] briefly reviewed the functions and activities of Pyrroloquinoline Quinone (PQQ) in treating osteoporosis and neuro injuries, which will provide new ideas for the study of osteoporosis and neuro injuries. With the increasing interest in shifting the “blinded use” of natural compounds for direct treating bone diseases paradigm in traditional medical practices to “one-compound-one-target” therapy or “compounds-targets” therapy, therapeutic benefits for various musculoskeletal diseases have been achieved. Therefore, we hope that this thematic issue will be beneficial for the vast readers and may serve as a good source of literature for scholars in the field of each relevant field.

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

Articular cartilage possesses no blood vessels, lymphatic vessels and neural tubes. Thus, the ability of articular cartilage to repair itself is very limited once it is damaged [1, 2]. Articular cartilage defects is a common clinical disease, but difficult to repair. Many strategies have been applied to enhance the cartilage defect repair with the ultimate aim which can fill the defects with the same morphological and functional repaired cartilage tissue [3]. The widely employed strategies in clinic were periosteal and perichondral tissue grafting, osteochondral allografting, chondrogenic cell transplantation, and subchondral drilling [4]. However, the immune rejection reaction and high cost of medical expense made the patients disappointed. Fortunately, the development of tissue engineering, which is a cell-based repair biomaterial engineering brings hope. The special issue aimed at the stem cells and scaffolds in cartilage tissue engineering. The content included the three main factors for cartilage tissue engineering, namely stem cells, scaffolds and stimulating factors. It not only provided the latest ideas and methods to design and fabricate the cartilage repair scaffolds, but also offer the helpful reference for the research of cartilage tissue engineering. In detail, different sources of stem cells made an important influence on the cartilage repair and they were widely applied in cartilage tissue engineering. Numerous researches using stem cells with chondrogenic potential (such as Mesenchymal Stem Cells, Adipose Stem Cells, etc) have suggested that the different scaffolds can support the proteoglycancontaining tissues and formation of type II collagen [5, 6]. Many physical (such as nanomaterials, stiffness, pores, etc) cues can drive stem cell differentiation into chondrogenic phenotype [7-9]. The mainly studied scaffolds in cartilage tissue engineering were hydrogel and electrospun fibers [10-12]. The formation mechanism, preparation techniques, and the influence on stem cells of these scaffolds were introduced systematically. The stem cells, scaffolds and stimulating factors had intrinsic relationships and influence each other, once they were applied in tissue engineering. In summary, the special issue presented a deep view of the research progress in cartilage tissue engineering.

Bio-immunotherapy is an emerging area for treatment of cancers and autoimmune diseases, which are difficult to cure with current regimens. Bio-immunotherapy includes the methods used to elicit, reactivate or reverse immune responses, promote the repairs of diseased tissues and restore the functions of cells, tissues or organs by applying biological responder modifiers (BRMs), cytokines and/or growth factors, immune cells, or stem cells. The aim of the thematic issue is to historically review the various types of the methods for bio-immunotherapy in research or clinical practice, reveal advantages and disadvantages for each approach, evaluate their potential efficacy for treatment of cancers or autoimmune diseases, and prospectively propose potential strategies to overcoming the limitations of current bio-immunotherapy approaches. The thematic issue will provide a comprehensive update on bio-immunotherapy beneficially for research scientists and clinical physicians.

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