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Many
neurological disorders, such as stroke, Parkinson’s disease and multiple
sclerosis, etc., are caused by the loss of neurons and glial cells. Both in vivo and in vitro, mesenchymal stem cells (MSCs) have their potential to
differentiate themselves to nerve cells, which provides a new train of thought
for the treatment of nervous system diseases. Compared with neural stem cells
(NSCs), the advantages of MSCs, such as being obtained conveniently, easy
separation, culture and proliferation in
vitro, no rejection for self out, etc., provide a much wider space to treat
nervous system diseases. Studies on the combination of Chinese Herbal Medicine
(CHM) and MSCs have revealed that CHM and some effective components could
activate endogenous stem cells and induce stem cells to differentiate into
neural-like cells in vitro and
promote angiogenesis. Traditional Chinese Medicine (TCM) has formed a unique
theoretical system after development for thousands of years. Guided by TCM
theories, researches on MSCs differentiation into neural-like cells directional
inducted by CHM create a new method for the application of CHM in the field of
MSCs. This review aims to summarize the latest research findings on MSCs
differentiation into neural-like cells directional inducted by CHM from the
viewpoint of syndrome differentiation and treatment.
INTRODUCTION
In the
field of stem cell research, TCM has a unique theoretical system and
application form. It has been reported that CHM and some effective components
have a promoting effect on the proliferation and differentiation of stem cells.
Compared with other revulsants or methods, CHM has many characteristics, such
as safety and comprehensive clinical application. TCM treatment emphasizes the
concept of holism, syndrome differentiation and treatment. CHM can directly act
on stem cells in the body and promote the proliferation and differentiation. It
can also influence the microenvironment, promote their survival and function,
adjust the body's immune function, reduce or eliminate the immune rejection.
Nowadays, many studies have shown that CHM can effectively induce MSCs
from different sources to differentiate to neural-like cells [1-3]. Guided
by TCM theories (the concept of holism, syndrome differentiation and treatment,
et al.), the study of the mechanisms of proliferation, differentiation and
resistance to damage of MSCs can bring great development for MSCs’ application
in nervous system diseases.
Characteristics of MSCs Differentiation into
Neural-like Cells
MSCs are the kind of adult stem cells that exist in a variety of
organizations, such as bone marrow, umbilical cord blood and umbilical cord,
the placenta tissue, amniotic fluid and adipose tissue [4-6]. They can
differentiate into ectomesenchymal series cells including ossification,
cartilage and fat cells [7-9], or non-mesoderm lineages such as Schwann-like
cells which play roles for the development, myelination and regeneration in the
peripheral nervous system [10-12]. MSCs were originally found in the
bone marrow [13]. Bone marrow is the main source.
MSCs can not only promote other cells to differentiate into neural-like
cells, but also differentiate into neural-like cells under certain conditions.
MSCs are capable to secret cytokines, chemokines and growth factors, which play
important roles in creating favorable microenvironments for proliferation of
neural cells at the injury site, hence enhance angiogenesis, synaptogenesis and
neurogenesis in the damaged brain tissue [14,15]. The microenvironment provided
by bone marrow mesenchymal stem cells (BMSCs) is beneficial for NSCs to
differentiate selectively into neuronal and astrocytic phenotype cells. BMSCs
not only induce neuronal differentiation of NSCs but also enhance the survival
of neurons. Soluble factors secreted by BMSCs are responsible for their effect
on the neuronal differentiation of NSCs [16]. BMSCs have capacity to cross the blood-brain barrier and migrate
into injured tissues systematically [17], and then they differentiate into
mesenchymal lineage cells, including neurons and non-neuronal cells in the
brain [18]. Hoda Jahani et al. [19] indicated that
MSCs cultured on nanofibrous scaffold had potential differentiation to neuronal
cells, electrospun scaffolds, particularly scaffolds with random nanofibers
indicating to have potential in promoting the differentiation of mesenchymal
cells.
Studies indicate that cells derived from bone marrow survive,
proliferate, migrate and can differentiate into glial and neuronal phenotypes.
Compared with NSCs, MSCs are easy to isolate from the small aspirates of bone
marrow that can be obtained under local anesthesia, capable of rapid
proliferation in culture, amenable to survive and integrate in the host brain,
and immunologically inert [20]. All the benefits provide a wider application
for MSCs in nerve tissue repairment.
The
Mechanism of the Differentiation of MSCs into Neural-like Cells Based on TCM Theories
After 5000 years of development, TCM has the complete theory system and
rich clinical practice experiences. The concept of holism, syndrome
differentiation and treatment are the two basic features of TCM. Essential qi
theory, yin-yang theory, five phase theory, zang-fu theory, et al. constitute its main theories (Table 1).
In essential qi theory, essence means the fundamental substance that
builds up the physical structure and maintains body function, especially
reproductive essence stored in the kidney. Shen [21] pointed that
kidney essence can correspond to embryonic stem cells and the kinds
of tissues and organs differentiated from ESCs. Zhang et al. [22] elaborated essence theory of TCM
from the perspective of stem cells. They considered
that the totipotent stem cells (TSCs) contain all
the congenital essence. By comparing the functions of TSCs and other
founded adult stem cells with the functions of proliferation, growth and
development, generation marrow and blood of the essence, we found that the
basic attributes of essence and stem cells were analogous (Figure 1).
In the field of TCM, qi refers both to the refined nutritive substance
that flows within the human body as well as to its functional activities. We
consider that the nutritive substance that qi mains is likely to cell health
factors. The functional activities now have been fully understudied via
acupuncture, qigong and kongfu. Blood is described as the red fluid circulating
through the blood vessels, which can nourish and moisten the whole body.
Essence and blood can promote mutually and transformate into each other. While the interaction between essence and
blood is achieved by the functional activities of qi (Figure 2).
Essence especially means the reproductive essence stored in the kidney.
Blood is mainly stored in the liver. In the five phase theory, the kidney
belongs to water, while the liver to wood. So on the relationship of mother and
child, the kidney (water) generates the liver (wood). In addition, the
warmth of kidney qi promotes the liver stronger. On the other hand, the blood
stored in the liver is derived into the kidney to generate essence duo to the
convergence of qi.
Brain is one of the extraordinary organs enclosed within the skull
where the marrow converges, and the spirit, mental activities as well as
thinking take place. Marrow is defined as an extraordinary organ including bone
marrow and spinal marrow, both of which are nourished by the kidney essence. Su Wen points out that
“The marrow is belongs to the brain”. Ling Shu says “At the beginning
of one generation, the essence generates firstly. After the
generation of the essence, the brain is produced”. Yixue Zhongzhong Canxi Lu
summarizes the theories as that “The brain is the sea of marrow, which
is generated by the Yin qi and Yang qi of the kidney”. So, it is clear that kidney essence is the
foundation of the brain’s generation (Figure 3). Therefore, essence, qi, blood, marrow
and brain form an interactive system. Kidney essence, qi and blood are the
material basis of brain’s growth and development. MSCs are
mainly derived from bone marrow; they not only have the characteristics of
essence, marrow and blood, but also have the functions of transformation
into various substances. So it can be
concluded that the application of MSCs in nervous system diseases would
play an unexpected role.
If the balance of Yin and Yang in zang-fu is
broken, the flow of qi and blood would be in disorder, the brain would be
damaged, nerve cells would be necrosis or apoptosis, the regulatory mechanism of proliferation, migration and differentiation
of stem cells would also be damaged. Therefore, the regulatory mechanism
of activation and repairmen of
MSCs is closely related to essence, marrow, qi and blood, and depends on the
coordination of them.
The Therapy Methods and Using
of Medication Based on the TCM Theories inducing Mscs Differentiated into
Neural-Like Cells
Traditional Chinese Medicine attaches importance to the holistic concept, emphasizing the unity of the whole and local, macro and micro environments. Also it emphasizes the theory of syndrome differentiation and treatment. The major TCM theories and Chinese herbs inducing MSCs differentiated into neural-like cells are summarized in Table 2.
Tonify Qi and reinforce the healthy Qi
The ancient Chinese sages said:"When there is sufficient health qi
inside, the pathogenic qi have no way to invade the healthy body".
Tonifying qi herbs can stimulate the healthy qi in
patients; sufficient healthy qi provides a guarantee for the
transformation of spirit. Astragaloside
IV (AS-IV) is the representative of qi invigorating drugs, and has been
widely used for the treatment of nervous
system diseases in China. AS-IV attenuated TLR4 expression through the
NF-kB signaling pathway in MSCs so as to promote the proliferation of MSCs
[23]. Further studies showed that MSCs
can differentiate into neurocyte-like and gliocyte-like cells in vitro. Wnt-1 gene and Ngn-1 gene played important regulatory roles during the
differentiation of the rat bone marrow-derived mesenchymal stem cells to
neurocyte-like
cells [24]. Astragalus injection
can induce the differentiation of MSCs into neuron-like cells and the process
of differentiation might be mediated by activation of Wnt signaling pathways [25].
Wu et al. [26] demonstrated that Ginsenoside Rg1 could strengthen the
spatial learning memory ability in dementia rats after transplanted with BMSCs.
Possibly, its mechanism might be related with the up-regulating mRNA expression
of nerve growth factor (NGF) in basal forebrain after BMSCs transplantation. It
has been proved that Shenqi Fuzheng
injection can induce hMSCs to differentiate into neurons in vivo in rats
with middle cerebral artery occlusion (mcao).
Immunohistochemical staining showed that Shenqi Fuzheng injection significantly increased the
differentiation of hMSCs to human neuron specific enolase (NSE),
neurofilament(NF) and glial fibrillary acid protein(GFAP) [27].
Tonify Qi and
activate blood circulation
“The YuanQi was deficiency, will not reach the blood vessels,
eventually lead to the
stagnation of blood and the formation of blood stasis.” The method of tonifying
qi and activating blood circulation has been commonly used in clinic for
treatment of nervous system diseases such as central infarction, cerebral
hemorrhage and so on. Recently, scholars have studied Chinese medicine and the
extracts in inducing the differentiation of bone marrow MSCs to neurocyte-like
cells and acquired some outcomes. Nie et al. [28] observed and
evaluated the effect of transdifferentiation of MSCs into nerve cells by
ultrafiltration membrane extract mixture from Angelica sinensis and Hedysarum
polybotrys. Results demonstrated that BMSCs changed neural-morphologically
after induction. The expression levels of NSE, nestin, NFP, MAP2, GFAP were
highest in the positive control group (P
< 0.05), followed by the ultrafiltration membrane extract mixture group (P < 0.05). Buyang Huanwu Tang
combined with MSCs transplantation could repair the injured blood vessels and
lesion tissues, the mechanism study showed that VEGF and Ki-67 expressions
were significantly up-regulated in the MSCs group and the combination group,
with significant differences as compared with the model group and the sham
operation group (P<0.05), and with the most strongest effect in the
combination group [29]. Naomai Yihao
Capsule has the function of tonifying qi, activating blood circulation, and
resolving phlegm so as to regulate the "sea of blood in brain". The
observation of Naomai Yihao Capsule
combined with BMSCs transplantation showed that Naomai Yihao Capsule could promote the angiogenesis and
neurological impairment recovery by increasing the expression of CD31 in the
brain tissue in focal cerebral ischemia rats which were administered with BMSCs
transplantation, and the effect was reinforced with the extension of treatment
time [30]. Zhang et al. [31] induced
bone marrow MSCs using Yiqihuoxue recipe
and found that Yiqihuoxue recipe
could express NSE, a marker of neurons, GFAP, a marker of glial cells, and
nestin, a marker of neural stem cells. These evidences indicate that Yiqihuoxue recipe can induce the
differentiation of bone marrow MSCs in
vitro.
Activate blood and
resolve stasis
At the acute phase of cerebral injury, the functions of qi and blood
are abnormal, blood stasis appear, which will lead to the necrosis or apoptosis
of neurons. The regulatory mechanism of proliferation, immigration, and
differentiation of neural stem cells would also be damaged. If blood stasis has
not been removed, there would no generation of new blood. Experiments have
proved that some Chinese herbs are anti-thrombolysis, they play an important
role in differentiating MSCs into nerve cells, so as to improve
microcirculation in central nervous system that might improve, repair and
rehabilitate from stroke and brain injury [32]. After induction by Danshensu, MSCs exhibited the typical
form of perikaryon with pyknotic cell body and prominence projected like that
of neuron. These cells were positively expressed in NSE, NF-M and nestin, and
negatively expressed in GFAP [33]. Salvianolate
inhibited the proliferation of human umbilical cord mesenchymal stem
cells(hUCMSCs) under high concentrations. Cells showed a neuron- like
morphology when treated with brain derived neurotrophic factor (BDNF) or
salvianolate combined BDNF. The contents of Ach and positive expression rates
of Nestin, NES and choline acetytransferase in high-dose and middle-dose
combination groups were significantly higher than those in low-dose combination
group and BNDF group (P<0.05).
There was no significant difference between the high- dose and middle- dose
combination groups(P>0.05) [34].
Extract of Ginkgo biloba(EGb761)
increased the human adipose-derived stem cells (hADSCs) proliferation, especially
on 3 d(P<0.05). EGb761 induced
hADSCs to neural differentiation, not to glial cell differentiation [35]. The
percentages of NSE-positive neuron-like cells in the different concentrations
of ginkgolide B were higher than the
percentage in the control group. However, there were no significant differences
between the different concentrations [36]. Zheng et al. [37] studied the
effects of total saponins of Panax
notoginseng (tPNS) on angiogenesis in rat bone marrow mesenchymal stem cells
(rBMSCs). The study showed that tPNS (100 μg/ml) significantly enhanced the mRNA
expression level of VEGF-A and Kdr compared to the control group, while they
had no obvious effect on the expression of Flt-1. tPNS (1 μg/ml and 100 μg/ml)
significantly increased capillary network forming of rBMSCs after endothelial
differentiation in Matrigel in vitro.
tPNS (50 μg/kg, 100 μg/kg and 150 μg/kg) also significantly increased
angiogenesis induced by the combination with implantation of rBMSCs and
Matrigel in vivo. Sodium Ferulate (SF),
as the main active constituent of Chuanxiong,
combined with BMSCs administration could facilitate BMSCs migration into the
ischemic brain by up-regulation of stromal cell-derived factor-1 alpha
(SDF-1α)/chemokine (CXC motif) receptor-4 axis after stroke. The combination
treatment of SF and BMSCs could not only promote expression of Glucose
transporter 1(Glut1) and Neuron-specific class III beta-tubulin (Tuj1) in the
periinfarct area, but also improve BMSCs expression of Glut1, GFAP and Tuj1.
Moreover, it showed that combination treatment could enhance the endogenous
expression of Tuj-1 in ischemic boundary zone [38]. A novel tissue inducible
nerve guide conduit, chitosan microspheres, has better biological compatibility
and tissue inducible function. The ligustrazine
released from the chitosan microspheres could promote MSCs to express NSE and
MAP2, the relevant marker molecule of nerve cells [39].
Tonify the kidney to
supply essence
The MSCs from bone marrow and NSCs from central nervous
system both belong to congenital essence. They can transform
into each other. Kidney-tonifying and essence-replenishing method may play
an important role to promote MSCs differentiation into NSCs. Plastrum Testudinis (PT), as an
important CHM to tonify the Kidney, was proved to induce MSCs to
differentiate into NSCs in vitro,
but not into neuron like cells or astrocytes [40]. Other study found that after
induced adult rats MSCs 12 h with PT, the
positive expression of neuron like cells NF reached the peak [41].
Rehmannia glutinosa polysaccharide (RGP) is one of the effective
components of CHM Rehmanniae, with the effect of tonifying the
kidney to supply essence. The detection of immunocytochemical stain and RT-PCR
method showed that neural cell markers were not expressed in the control group,
but expressed in the other groups. Positive cells rate of nestin and NSE in the
RGP induction group was higher than theβ-mercap
toethanol(BMT) induction group and the BDNF induction group (P<0.05) and positive cells rate of
GFAP lower (P<0.05), but there was
no difference between the BMT induction group and the BDNF induction group in
nestin, NSE and GFAP positive cells rate. The all cells were Notch 1 protein
positive in RGP induction group, which were reduced gradually over time, according
to immunocytochemistry. Western blot results showed that the contents of NICD
was up-regulated 24 h after RGP induction and decreased gradually, and even
fell below the baseline level and significantly lower than control group at 5th
day (P<0.05) [42-44]. Lycium barbarum polysaccharide also has
inductive effect on differentiation of BMSCs into neurons of adult rats in
vitro. After induction for 4 hours, some BMSCs showed processes extended
obviously. Twenty four hours later, the differentiated cells showed
significant processes, and the processes were connected to each other, showing
typical neural cell morphology. In these cells, the expression of microfilament
and nestin was positive, but GFAP was negative [45]. Kuang et al.
[46] observed the ability of Sanjia Fumai
Tang medicated serum in inducing the differentiation of MSCs into
neurons in vitro in adult rats. The
results found that with the extension of the induction time, the cell
morphology of MSCs changed obviously, the cell size decreased, the cytoplasm
contracted to the nucleus, the morphology changed into circular, forming a
network like structure and neuron like cells increased. But the same
change did not be observed in the control group. After 12 hours’ induction,
neuron cell’s positive rate reached its peak, and there were still neuron cells
survived after 7 days, and the longest survival time was the Sanjia Fumai Tang group.
Open the orifices to
induce resuscitation
The method of opening the orifices to induce resuscitation for the
treatment of cerebral infarction has a long history, and the curative effect is
exact. Both the method and activated NSCs which are usually in a resting state
have particular but similar effect on promoting the nerve regeneration.
Xiao et al. [47,48]
directly induced 5-10 generation MSCs with culture medium containing
musk polypeptide in vitro, the results showed that the cells changed into neuron
like cells, immunohistochemical sample also showed that the neuronal cell
NSE and NF induced, nest protein expressed positively, GFAP expressed
negatively. Neuron like cell count analysis found that the
percentage of NSE and NF-H positive cells were higher after
inducted by musk polypeptide. As inducers, Gastrodia elata similarly could induce most of MSCs to
differentiate into neuron-like cells, revealing cytodendrite. By immunochemical
staining, cells showed positive NSE, nestin, and negative of GFAP [49]. Niupo Zhibao Weiwan(NZW) was varied from
Zhibaodan. The study found that NZW
medicated serum could enhance the expression of Brdu and NF in MSCs
transplantation region, and the enhancement effect can
last 6 weeks [50,51].
Induce resuscitation
by Fu-unblocking therapy
The method of inducing resuscitation by Fu-unblocking therapy can not
only modulate the function of stomach, spleen, lung, liver and other
viscera, but also improve permeability of the blood-brain barrier, relieve
cerebral edema, and promote nerve
regeneration. Rhubarb aglycone
can decrease the degradation of basal lamina Col Ⅳ and
the permeability of brain micrangium in cerebral ischemic rats with BMSCs
transplantation by means of regulating the balance of matrix
metalloproteinase-9 (MMP-9), increasing the expression of tissue inhibitor of
metalloproteinase-1 (TIMP-1) [52]. Rhubarb
aglycone also can advance the time of protecting neurocytes after BMSCs
transplantation. The mechanism may be related to the fact that it can
up-regulate the expressions of NGF and glial cell-line derived neurotrophic
factor (GDNF) in earlier phase and increase NGF expression in metaphase and
anaphase [53]. 100 μmol/L baicalin
can promote amplification of cord blood MSCs in vitro. After culture
cultured for 4 weeks, the expression of neuron specific enolase and microtubule
associated protein 2 were lower in the blank control group and
β-mercaptoethanol group compared to the baicalin
group (P < 0.01), and no significant difference was found in the
co-culture group(P > 0.05). All these indicated that baicalin also can induce the differentiation of cord blood MSCs
into neuron-like cells [54,55]. Berberine
was also approved with the same effect of inducing adult rat MSCs to
differentiate into neuron-like cells in
vitro [56].
Views and Prospects
At present, researchers have carried out many theoretical discussions
and experimental studies in inducing the differentiation of mesenchymal stem
cells into neural-like cells via the use of TCM thoughts from different
angles, such as the composition of CHM monomer, single CHM and effective component, and have achieved encouraging results.
However, in the process of these current studies, the focus was usually partial to some
effective components of the composition, single herb or the compound, which led to the neglect of
the concept of holism of TCM theory. So the theory of medicinal
properties and pharmacodynamics of CHM should be combined with the basic
theories of TCM. Only by means of getting research ideas from the viewpoint of
the holistic concept of TCM
theory and combining with modern research methods, could the
development of modernization of TCM be better.
CONFLICTS OF INTEREST
The authors declare that there is no conflict of interests regarding
the publication of this article.
AUTHOR CONTRIBUTIONS
Lijun Qiao drafted
the manuscript. Lijun Qiao, Aili Lu, Mei Feng, Caiwen Qian and Lingbo Hou
retrieved the literature together. Jun Zhang,Tongxiang Lin,Yuanqi Zhao reviewed
this manuscript. All authors approved the final version of this
paper.
ACKNOWLEDGEMENTS
This study was funded by the Natural Science Foundation of Guangdong
Province (No. 2015A030310436) and the Research project of Guangdong Provincial
Traditional Chinese medicine administration (No. 20151210). The foundation
staff had no role in study design, data collection and analysis, decision to
publish, or preparation of the manuscript.
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