ISSN (Print): 1574-888X
ISSN (Online): 2212-3946
Volume 15, 8 Issues, 2020
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ISSN (Print): 1574-888X
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Special Issue Submission
Stem Cells from Human Exfoliated Deciduous Teeth: Waste to Wealth
Guest Editor(s): Nazmul Haque
Submit Abstract via Email
(Hacettepe University Institute of Health Sciences, Department of Stem Cell Sciences, Center for Stem Cell Research and Development, Ankara, Turkey.)
Has contributed: “From Stem Cell Biology to The Treatment of Lung Diseases.”
48 Articles Ahead of Print are available electronically
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.,  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.,  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
As two critical substrates of phospholipase Cγ (PLCγ) family, PLCγ1 and PLCγ2 play a crucial role in immune reactions.
Liu et al.,  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., 
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., , 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.,  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.,  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.,  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
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 , 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 . 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 . 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.  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.  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. , 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.
 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.  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.  focus on the use of electrical stimulation to modulate stem cell functions.
In another paper, Zhang et al.  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.,  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.,  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.,  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.,  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.,  reviewed studies for the biological functions of myricitrin and its anti-inflammatory role in bone loss.
Wen et al.,  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 , CD44 , CD49 , Lgr5 , CD133 
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  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 .
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 . 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 . 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 , 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)  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  and highly remodeling
tissue of endometrium, considering “MSC” as rare cells . Poggi & Zocchi  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 . Engineering strategies, including manipulation of “MSC” microenvironment,
were found to be an important approach for dental , 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.  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.  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.  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.  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 . The widely employed strategies in clinic were periosteal
and perichondral tissue grafting, osteochondral allografting, chondrogenic cell transplantation, and subchondral drilling
. 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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