Li et al.

Stem Cell Research & Therapy (2022) 13:472

https://doi.org/10.1186/s13287-022-03152-z

REVIEW Open Access

The potential of plant extracts in cell therapy

Caifeng Li1, Zhao Cui2, Shiwen Deng1, Peng Chen1,3*, Xianyu Li1* and Hongjun Yang1,3*

Abstract
Cell therapy is the frontier technology of biotechnology innovation and the most promising method for the treat-
ment of refractory diseases such as tumours. However, cell therapy has disadvantages, such as toxicity and poor
therapeutic effects. Plant extracts are natural, widely available, and contain active small molecule ingredients that are
widely used in the treatment of various diseases. By studying the effect of plant extracts on cell therapy, active plant
extracts that have positive significance in cell therapy can be discovered, and certain contributions to solving the cur-
rent problems of attenuation and adjuvant therapy in cell therapy can be made. Therefore, this article reviews the cur-
rently reported effects of plant extracts in stem cell therapy and immune cell therapy, especially the effects of plant
extracts on the proliferation and differentiation of mesenchymal stem cells and nerve stem cells and the potential
role of plant extracts in chimeric antigen receptor T-cell immunotherapy (CAR-T) and T-cell receptor modified T-cell
immunotherapy (TCR-T), in the hope of encouraging further research and clinical application of plant extracts in cell
therapy.
Keywords: Cell therapy, Plant extracts, Stem cell, CAR-T, TCR-T

Introduction and adipose-derived stem cells (ASCs), among others,

As the frontline of biotechnological innovation, cell and have significant therapeutic effects in cardiovascular,
therapy has a significant influence on medical treatment neurological, skeletal, and autoimmune diseases [4, 5]. In
and provides new sights for difficult diseases [1]. Cell addition, immune cell therapy, represented by chimeric
therapy mainly includes stem cell therapy and immune antigen receptor T-cell immunotherapy (CAR-T), and
cell therapy. Stem cells can be acquired from embryonic T-cell receptor modified T-cell immunotherapy (TCR-
tissue, foetal tissue, adult organism, and induced pluri- T), has shown potential efficacy in multiple myeloma and
potent stem cells (iPSCs) [2, 3]. According to develop- other haematologic malignancies as well as in some solid
mental stage, stem cells include pluripotent stem cells tumours [6]. Cell therapies have a large latent capacity
(PSCs) and adult stem cells. Among them, PSCs include under the development of modern science and technol-
embryonic stem cells (ESCs) and iPSCs [3], which are ogy. However, cell therapy itself still has deficiencies in
pluripotent. However, ESCs have ethical issues, and the practice, such as side effects, inflammatory factor storms
probability of reproductive cloning and tumour forma- caused by excessive immune responses and poor effects
tion limited the application of iPSCs [3]. Adult stem cells in some patients. As a result, combining it with other
overcome these problems of PSCs, which contain mes- drugs may be a way to solve this problem. Additionally,
enchymal stem cells (MSCs), neural stem cells (NSCs), protein cytokines and antibodies have been widely used
in cell culture and clinical treatment, with disadvantages
such as toxicity, and high cost. Therefore, at present,
*Correspondence: [email protected]; [email protected]; looking for alternative plant extracts that can be used as
[email protected]
1
growth factors and adjuvant therapies in cell therapy is a
Beijing Key Laboratory of Traditional Chinese Medicine Basic Research On
Prevention and Treatment for Major Diseases, Experimental Research Center,
promising approach [7].
China Academy of Chinese Medical Sciences, Beijing 100700, China Hormesis effects on stem cells have been observed,
Full list of author information is available at the end of the article mainly in the use of drugs (e.g. metformin, atorvastatin,

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Li et al. Stem Cell Research & Therapy (2022) 13:472 Page 2 of 14

and isoproterenol), dietary supplements/medicinal The effect of plant extracts on stem cell therapy
plant extracts (e.g. berberine), and endogenous drugs The effect of plant extracts on MSCs
(e.g. estrogen) [8, 9]. Among them, plant extracts are an MSCs exist in almost all postnatal human tissues. The
important source of bioactive small molecules, which major sources of adult MSCs are mainly from bone mar-
are mainly derived from herbal plants, and include flavo- row, adipose tissue, etc. [7, 15]. Compared with ESCs,
noids, alkaloids, polysaccharides, volatile oils, etc. Plant MSCs are easier to isolate and culture in vitro, and more
extracts play an important role in disease treatment, importantly, there are fewer ethical issues. Furthermore,
especially in cancer and infectious diseases. Herbal ther- due to their HLA-DR-negative feature, MSCs do not have
apy is a traditional medical practice that has long been immunogenic in therapy [7]. MSCs are characterized
used to treat a variety of diseases. Herbal medicine is safe by different sources, isolation methods, and epigenetic
and affordable [7]. It is a promising alternative approach changes during growth. They can be differentiated into
with a significant effect on alleviating patient disease. osteocytes, neurons, and angiogenesis, through stimula-
Therefore, studying the effects of plant extracts in cell tion with plant extracts (Fig. 1).
therapy and digging out active plant extracts in herbal
medicines can provide guidance for adjuvant therapy Proliferation effect
combined with cell therapy. Many plant extracts, such as Foeniculum vulgare [16],
The application of plant extracts in cell therapy has Ferula gummosa [17], amentoflavone (Selaginella tam-
gradually increased with the rapid development of cell ariscina (P. Beauv.) Spring) [18], gastrodin (Gastrodia
therapy. For example, the increased therapeutic effects of elata Bl.) [19], and resveratrol (Polygonum cuspida-
stem cells induced by plant extracts have been reported tum Sieb. et Zucc.) [20], can significantly increase bone
in studies of Alzheimer’s disease [10], chronic kidney marrow-derived human MSCs (BM-hMSCs) prolifera-
disease [11], and stroke [12], and the therapeutic effects tion. In addition, ginsenoside Rg1, which is an effective
of immune cells induced by plant extracts have been compound in Panax ginseng, Panax notoginseng, and
reported in diseases such as non-small-cell lung cancer American ginseng, can also promote cell proliferation
and liver cancer [13, 14]. This review describes the effects [21]. Apple ethanol extract promotes proliferation of
of plant extracts, mainly herbal extracts, in cell therapy hASCs and human cord blood-derived MSCs via ERK
approaches and clarifies the potential mechanisms of signalling [22]. Tinospora cordifolia and Withania som-
action when possible. nifera are traditional Ayurveda medicinal materials in

Fig. 1 Sources of MSCs and their proliferation, differentiation, angiogenesis, antilipogenesis, and antioxidant stress effects stimulated by plant
extracts
Li et al. Stem Cell Research & Therapy (2022) 13:472 Page 3 of 14

India that are reported to improve cell proliferation Osteogenic effects through Wnt signalling pathways
ability and activity, as well as reduce cell apoptosis and Flavonoids of epimedii(Epimedium brevicornum Maxim.,
postpone aging [23]. ZD-I is a prescription composed etc.) were found to increase the rates of osteogenic activ-
of seven traditional Chinese medicines (TCM). It has ity through the BMP or Wnt-signalling pathway [38]. In
stimulatory effects on the proliferation of hMSCs [24]. addition, Angelica sinensis polysaccharide can enhance
Viscum album induces primitive placenta-derived the osteogenic differentiation of rat BM-MSCs cultured
MSCs (PDSCs) with remarkable proliferative properties in high-sugar and guide bone regeneration in type 2 dia-
through autophagy mechanism. Specifically, Viscum betes animal model which chained to the Wnt/β-catenin
album can regulate the cell cycle to make PDSCs self- signalling pathway [39]. Ginkgo biloba and its main com-
renewal and regulate the induction of survival factors, ponent ginkgolide B accelerate osteoblast differentiation
apoptosis and autophagy to reduce cell death [25]. and the formation of bone via Wnt/β-Catenin signalling
[40] (Fig. 2). Berberine (Coptis chinensis Franch.) [41] and
salvianolic acid B (Salvia miltiorrhiza Bge.) [42, 43] pro-
Differentiation effect mote osteogenesis in BM-MSCs through Wnt/β-catenin
Osteogenic effects signalling and strengthen Runx2 expression. Salvianolic
Osteogenic effects via transcription factors acid B influences the ERK signalling pathway and lower
Foeniculum vulgare, Ferula gummosa, and amentofla- PPARγ mRNA, accelerating the osteogenesis of MSCs.
vone can significantly increase the alkaline phosphatase The osteogenic-related genes can be strengthened under
(ALP) activity of hMSCs and promote BM-hMSC dif- the induction of naringin, and the expression of Notch1
ferentiation into osteoblasts [16–18]. Dipsacus asper can be up-regulated at the same time, and activation Wnt
and its ingredients hedraganin-3-O-(2-O-acetyl)-α-l- signalling activation [44].
arabinopyranoside enhance osteoblastic differentiation
not only by inducing ALP activity but also by induc-
ing bone sialoprotein and osteocalcin expression [26]. Osteogenic effects through BMP signalling pathways
Moreover, Fructus Ligustri Lucidi effectively activated Ginkgo biloba has been found to enhanced Runx2
ALP, reduced the osteogenic differentiation time of expression and regulated BMP4 in BMP signalling [45].
MSCs, and up-regulated the expression of osteogenic Moreover, harmine [33], silibinin(Silybum marianum
related factors such as catenin, BMP2, cyclin D1, mem- (L.) Gaertn.) [46], and genistein(Genista tinctoria Linn.,
brane matrix metalloproteinase, osteoprotegerin and etc.) [47] activate the BMP and Runx2 pathways. Duhuo
T-box 3 [27]. Poncirin (Poncirus trifoliata (L.) Raf ) Jisheng decoction and its effective component Ligusticum
[28], Panax notoginseng saponins [29, 30], and naringin Chuanxiong can activate Smad 1/5/8 and ERK signal-
(Citrus grandis) [31, 32] decreased peroxisome prolif- ling, increase the osteogenic effect of MSCs, and improve
erator-activated receptor γ (PPARγ) 2 mRNA levels, BMP-2 and Runx2 [48] (Fig. 2).
while Panax notoginseng saponins raised the levels of
ALP, Cbfa 1, OC, BSP, OPG, β-catenin, and cyclin D1.
Harmine (Peganum harmala L.) increased ALP activ- Osteogenic effects through MAPK signalling pathways
ity and up-regulated osteocalcin expression. Moreover, Most of the plant extracts used in the study of MSCs
harmine can up-regulate osterix [33]. The combination osteogenesis are TCM monomers. Icariin (Epimedium
of epigallocatechin-3-gallate [34] and bone inducer brevicornum Maxim., etc.), amentoflavone and quercetin
can up-regulate BMP2 and enhance bone formation. promoted osteogenesis via the JNK and p38 MAPK path-
Gastrodin [19] improved ALP, OCN, COL I, and OPN ways (Fig. 2). Icariin also phosphorylates ERK, and stimu-
while reducing ROS. Fucoidan enhanced osteogenic lates PI3K-AKT-eNOS-NO-cGMP-PKG pathway in bone
specific marker genes, such as ALP, osteopontin, type I marrow stromal cells [18, 49, 50]. Quercetin is a flavonoid
collagen, Runx2, and osteocalcin in ASCs [35]. Querce- that can also activate ERK signalling pathways, decrease
tin (Sophora flavescens Ait.) can increase Osx, Runx2, the aging and oxidative stress in MSCs, and promote
BMP2, Col1, OPN and OCN, and enhance osteo- osteogenic differentiation [51, 52]. Fucoidan can induce
genic differentiation [36]. BuShenNingXin decoction osteogenic differentiation, activate ERK and JNK mainly
(BSNXD) up-regulated ALP and collagen type I, osteo- through BMP2 Smad 1/5/8 signalling, and regulate osteo-
calcin, Runx2, and osterix. Furthermore, BSNXD was genic differentiation markers [53, 54]. One study showed
shown to reduce the quantity of adipocyte and PPARγ that resveratrol enhanced cell renewing by inhibiting cell
mRNA [37]. A summary table of plant extracts that aging at a low concentration, while it inhibits cell self-
stimulate osteogenesis of MSCs is shown in Additional renewal by up-regulating cell senescence, doubling time,
file 1: Table S1. and S-phase arrest at a high concentration. In addition, it
Li et al. Stem Cell Research & Therapy (2022) 13:472 Page 4 of 14

Fig. 2 Plant extracts that affect MSCs osteogenesis by regulating intracellular signalling pathways. Ginkgolide B, Panax notoginseng saponins,
berberine, and salvianolic acid B regulate axin, β-catenin, and TCF in the Wnt signalling pathway; Ginkgo biloba, harmine, silibinin, genistein, and
Ligusticum chuanxiong regulate BMP, Runx2 and Smad 1/5/8 in the BMP signalling pathway; Resveratrol, icariin, amentoflavone, quercetin, and
fucoidan regulate p38, ERK1/2, and JNK in the MAPK signalling pathway

can stimulate MSCs and promote osteoblast differentia- upregulate NSE, MAP-2, GAP-43, NCAM, and SYN-1
tion by acting on ER-dependent mechanisms and activat- genes [21]. Another study showed that gisenoside Rg1
ing ERK1/2 [20, 55, 56]. can promote neural differentiation in mouse ASCs by
miRNA-124 signalling pathway [63]. Similarly, radix
Neurogenic effects Angelicae sinensis can also induce adipose-derived MSCs
Mucuna gigantea grows natively in Hawai ‘i. It was to differentiate into neuron-like cells [64]. In Ayurvedic
recorded that it can be used to treat kampavata (excita- medicine, dhanwantharam kashayam is considered a
tory paralysis) [57]. Mucuna gigantea can promote growth stimulant for children, which can promote nerve
proliferation feature, nestin, and β-III tubulin mRNA regeneration [65].
expression in MSCs [58].
A study using human umbilical cord Wharton’s Jelly- Angiogenesis effects
derived MSCs (WS-MSCs) showed that Salvia miltio- Treatment of hMSCs with olive leaf extract promoted the
rrhiza increases the expression of nestin, β-tubulin, differentiation of cells into endothelial cells and develop-
neurofilament, GFAP, and neurite outgrowth-promoting ment of the tubular construction needed for angiogen-
protein [59]. Another study in rat BM-MSCs showed esis. At the same time, olive leaf extract can promote
that Salvia miltiorrhiza promotes Mash-1 and NGN-1 VEGF, PCAM, PDGF, and VEGFR-1 [7]. Curcumin is an
induced mRNA expression of TUJ-1, NF, and synapto- antioxidant and anti-inflammatory substance in turmeric.
physin [60]. Its ethanol extracts can increase the expression of CD34,
Ginkgolide B and Astragalus mongholicus can increase CD133, and VEGFR2 to cause ASCs to proliferation and
NSE-positive neuron-like cells and GFAP-positive astro- differentiation into endothelial progenitor cells [66]. In
cyte-like cells to promote MSCs differentiation into the animal hindlimb ischaemia model, fucoidan can pro-
nerve cells [61, 62]. Moreover, Astragalus mongholi- tect MSCs from oxidative stress and enhance angiogen-
cus also enhances the expression of the Wnt-1 gene and esis. Another study showed that fucoidan can inhibit the
Ngn-1 gene [62]. Ginsenoside Rg1 was found to acceler- cell death caused by MSCs ischemia, and adjust the lev-
ate the differentiation of neural phenotype in hASCs and els of apoptosis-related proteins and cellular ROS mainly
Li et al. Stem Cell Research & Therapy (2022) 13:472 Page 5 of 14

by MnSOD and Akt pathways [67]. In addition, through MSCs. However, some studies have demonstrated that
ERK-IDO-1 signalling cascade, it increases the prolifera- plant extracts have side effects. Cimicifugae Rhizoma,
tion potential and the expression of cell cycle-associated also called Shengma in China, affects the vita of dental
proteins, and enhances the immunoregulation activity of stem cells, and has side effects on the oral cavity at a high
MSCs [11]. Carica papaya leaf extract, rich in papain, was content [78]. Additionally, Asiasarum radix is the same as
found to enhance the composition of IL-6 and stem cell Cimicifugae Rhizoma [79]. As mentioned above, Fructus
factors related to platelet production in vitro [68]. Ligustri Lucidi has an osteogenesis effect. Nevertheless,
Fructus Ligustri Lucidi in a dose of more than 200 μg/mL
Anti‑adipogenic effects has cytotoxicity to MSCs [27].
Some plant extracts also have anti-adipogenic effects
on MSCs. The results of one study confirmed that the
The effect of plant extracts on NSCs
antioxidant action of Tithonia diversifolia may influ-
Endogenous NSCs are abundantly in the subventricular
ence the expression of HO-1. More importantly, it may
region of the hippocampal granular area and the germinal
regulate carbohydrate and fat metabolism by repressing
area of the cerebrum. They differentiate cells according to
adipocyte differentiation through activating AMPK [69].
the needs of brain structure and function [80]. NSCs are
In an experiment using MSCs, after stimulation with
primarily used to remedy central nervous system injury
aloe-emodin, many indicators were reduced, including
and degenerative diseases. There are two intervention
resistin, adiponectin, aP(2), lipoprotein lipase, PPARγ,
strategies involving NSCs. One strategy involves using
and TNFα, which influence adipogenic pathways [70].
endogenous NSCs to repair the diseased site, but endog-
Quzhisu can repress adipogenic differentiation of BM-
enous NSCs are not sufficient and prefer to differentiate
MSCs by downregulating PPARγ [71]. Similarly, flavo-
into gliocytes instead of neurons; the other strategy is
noids of epimedii like Quzhisu downregulate PPARγ, and
transplantation of exogenous NSCs [61]. However, it is
can also decrease C/EBP-α [72].
difficult to control the survival, replication, and differen-
tiation of exogenous NSCs into local nerve cells. Sources
Antioxidant stress effects
of NSCs include human ESCs, human iPSCs, human foe-
Undaria pinnatifida, Myrtus community L. and Cirsium
tal brain-derived neural stem/progenitor cells, and direct
setidens showed antioxidant stress effects in MSCs. Und-
reprogramming of astrocytes. According to their func-
aria pinnatifida, also called Mi-Yoek in Korea, is con-
tions, they can be divided into pluripotent and multi-
sidered a healthy food. The anti-aging effect of Undaria
potent cell types [81]. Plant extracts play an important
pinnatifida in BM-MSCs was researched. The results
part in promoting the proliferation and differentiation
showed that after ­H2O2 treatment, it had the effect of
of NSCs into new neurons. The Notch, Wnt, BMP, and
antioxidant stress, and could decrease aging and improve
sonic hedgehog signalling pathways have been the most
the differentiation potential of cells by controlling ROS
studied [82].
[73]. In addition, icariin protected rabbit BM-MSCs from
oxygen, glucose, and apoptosis via inhibition of ERs-
mediated autophagy associated with MAPK signalling Proliferation effect
[74]. Furthermore, residues from the production of Myr- Ginsenosides Rg1 advances the incorporation of Bromo-
tus community L. can counteract the appearance of aging 2-deoxyuridine and the expression of nestin and vimen-
phenotypes in ASCs, reduce oxidative stress and inflam- tin in NSCs, and promotes the proliferation of NSCs
mation, and enhance the expression of genes related to [83]. In addition, ginsenoside Rd can enhance the prolif-
pluripotency [75]. The authors also studied the genetic eration of NSCs in vivo and in vitro. It can enhance the
programs responsible for cellular senescence in human size and quantity of neurospheres [84]. After oxygen and
ASCs exposed to oxidative stress and found that in the glucose deprivation (OGD) /r injury in vitro, resveratrol
cells stimulated by Myrtle, the SA-β-Gal positive cells up-regulated the survival and proliferation of NSCs, and
and the cell cycle regulation genes were decreased, while increased patched-1, smoothened (SMO) and Gli-1 [85].
TERT and c-Myc genes were increased [76]. Cirsium Meanwhile, resveratrol can reduce the damage and raise
setidens [77] has a suppressive effect on cell injury by reg- the proliferation of NSCs by promoting Nrf2, HO-1 and
ulating oxidative stress and repressing apoptosis-related NQO1 [86]. Artesunate is a derivative of artemisinin
signalling pathways. from Artemisia annua [87]. It can inhibit transcription by
inducing Foxo-3a phosphorylation, then downregulating
Adverse p27kip1, and enhancing the proliferation of NSCs in the
The above studies have shown that certain plant extracts infarcted cortex through PI3K/AKT signalling transduc-
can promote the proliferation and differentiation of tion [88].
Li et al. Stem Cell Research & Therapy (2022) 13:472 Page 6 of 14

Differentiation effect increased BMPR IB. The p-Smad1/5/8 expression indi-

Wnt/β‑catenin pathway cates that ( +)-Cholesten-3-one may influence the BMP
The role of ginkgolide B has been mentioned above, it signalling [98].
also can enhance the differentiation of NSCs after cer-
ebral ischemia and may improve neural function by
Notch signalling pathway
increasing the expression of BDNF, EGF, and SOCS2
Astragaloside IV is an ingredient in Astragalus membran-
[12]. Ginkgo biloba extract and Ginkgolide B, was
aceus. Astragaloside IV leads NSCs to β-tubulin III ( +)
found to accelerate cell cycle exit and neuronal dif-
and GFAP ( +) cells through the Notch signalling path-
ferentiation in NSCs. Furthermore, ginkgolide B up-
way [10]. Moreover, in an in vivo study, astragaloside IV
regulated the nuclear level of β-catenin and activated
can promote proliferative cells(BrdU+), premature neu-
the classical Wnt to promote neuronal differentiation
rons ­(DCX+), early proliferative cells (­BrdU+/DCX+),
[89]. Curcumin (Curcuma aromatica Salisb.) has some
proliferative radial Glia-like cells ­(BrdU+/GFAP+), and
problems with pharmacokinetics and pharmacodynam-
regulate the homeostasis of the CXCL1/CXCR2 signal-
ics. Thereby Tiwari SK et al. prepared curcumin nan-
ling pathway [99].
oparticles and found that they can activate the classic
Wnt/β-catenin pathway to lead to human neurogenesis
[90]. Icariin is an important biologically active ingre- Others
dient extracted from Epimedium and has neuropro- Panax notoginseng saponins notably increased NSCs pro-
tective properties. Icariin treatment enhanced NSCs liferation and the expression of nestin/BrdU, Tuj-1, and
neurosphere formation and promoted the expression of vimentin mRNA in hippocampal NSCs. And the results
nestin, β-III-tubulin and GFAP. Icariin-regulated genes indicate that Panax notoginseng saponins may promote
participate in pathways including the Wnt and bFGF the proliferation and differentiation of NCSs after OGD
signalling [91], ERK/MAPK signalling [92], and BDNF- in vitro by increasing the area density, optical density
TrkB-ERK/Akt signalling pathway [93]. and the number of nestin/BrdU, nestin/vimentin, and
nestin/tuj-1 positive cells [100]. One study investigated
the effects of tetramethylpyrazine, an active element of
PI3K/AKT signalling pathway
Ligusticum Chuanxiong, which promotes the differen-
One study evaluated the function of salvianolic acid B
tiation of NSCs into neurons, increases the phosphoryla-
on the differentiation, proliferation, and neurite growth
tion of ERK1/2, and reduces the phosphorylation of p38
of mouse NSCs. The proper dose of salvianolic acid B
[101]. Baicalin could increase MAP-2 positive cells and
promoted the quality of NSCs and neurospheres, and
decrease the number of GFAP stained cells. Meanwhile,
accelerates the growth of neurites of NSCs and their dif-
p-STAT3 and Hes1 were downregulated, and NeuroD1
ferentiation into neurons [94]. Zhuang P et al. selected
and Mash1 were upregulated. These results suggested
45 kinds of ingredients from TCM widely applied in
that baicalin can promote neural differentiation but
the clinical treatment of stroke in China and examined
inhibit the formation of glial cells. Its role in promoting
their proliferation-inducing activity on NSCs. Finally, it
neurogenesis is related to STAT3 and bHLH genes [102,
was found that salvianolic acid B maintains NSCs self-
103]. Earlier research on NSCs showed that Buyang-
renewal and promotes proliferation through the PI3K/
huanwu decoction can promote cell growth and differ-
Akt signalling pathway [95]. Salidroside is an ingredient
entiation, increase neurofilament (NF) positive cells and
extracted from the plant Rhodiola rosea L. It can inhibit
GFAP positive cells, and promote intracellular ­Ca2+ con-
hypoxic NSCs injury by increasing miR-210, thereby
centrations [104, 105]. Jiaweisinisan has antidepressant
repressing BTG3 and influencing PI3K/AKT/mTOR
effects, promotes hippocampal neurogenesis after stress
signalling pathway [96]. The protective effect of berber-
damage, and significantly increases nestin, β-tubulin-III,
ine on OGD-treated cells via inhibiting the cell cycle. It
and GFAP [106].
can decrease cyclin D1, p53 and caspase 3, increase the
phosphorylation level of p-Bad/tBad, and upregulate
PI3K and Akt [97]. The effect of plant extracts on ESCs
ESCs can be obtained from the inner cell mass of a
blastocyst. It has the characteristics of in vitro culture
BMP signalling pathway
capacity, immortal cell proliferation, self-renewal, and
( +)-Cholesten-3-one(Serratula) induced NSCs dif-
multidirectional differentiation [107]. Using ESCs to dif-
ferentiation into dopaminergic neurons and promoted
ferentiate into different cell models is a promising drug
tyrosine hydroxylase, dopamine transporter, dopa
discovery method and technology [108]. Kami-Shoyo-
decarboxylase, dopamine secretion, and evidently
San is a TCM that can protect neuronal apoptosis in
Li et al. Stem Cell Research & Therapy (2022) 13:472 Page 7 of 14

ESCs by promoting brain-derived neurotrophic factor/ damage to human keratinocyte stem cells, and effectively
tropomyosin receptor kinase B signalling pathway [109]. enriched the p53- specific ligasing ability of the mouse
double minute 2 homologue in UVB irradiation-induced
The effect of plant extracts on iPSCs p53 activation. Likewise, zingerone (Zingiber officinale
iPSCs have characteristics similar to those of ESCs in Rosc.) [125] can protect the epidermis by restraining the
terms of unlimited self-renewal and differentiation UV damage mediated by p42/44 MAPK and p38 MAPK.
capabilities. Plant extracts induce iPSCs production In other stem cells, Ginkgo biloba[126, 127] activates tel-
and apoptosis. The Sagunja-tang herbal formula can omerase through PI3k/Akt signalling pathway to delay
efficiently produce iPSCs from human foreskin fibro- the aging of endothelial progenitor cells. Additionally,
blasts via transcription factors [110]. Prunellae Spica starting from telomerase, TSY-1 [128] increases telomer-
and Magnoliae cortex-mediated apoptosis of undiffer- ase activity in ­CD34+ haematopoietic stem cells.
entiated iPSCs was found to be p53-dependent, and to
have potent anti-teratoma activity, with no genotoxicity Immune cell therapies
toward differentiated cells. Therefore, these compounds Adoptive cell therapy (ACT) is a kind of immunotherapy
can be used for iPSC-based cell therapy to induce apop- that is genetically modified T-cells to deliver a CAR or
tosis of possible undifferentiated iPSCs and prevent the TCR. To a certain extent, mutated cancer cells provide
occurrence of teratomas [111, 112]. many peptides that are not found in natural cells, which
Plant extracts can induce differentiation of iPSCs into brings a potential target for constructing a new antigen
nerve cells. Salvia miltiorrhiza can significantly increase screening system, and promotes the development of
the expression of nestin and microtubule-associated pro- ACT, making CAR-T and TCR-T treatment become the
tein 2 (MAP2) genes and proteins, and induce the dif- most prospective way to treat cancer. However, ACT has
ferentiation of iPSCs into neurons [113]. Plant extracts great differences in the treatment of various tumours
also have an improved effect on the nerve cell model dif- types, and there are still some shortcomings that need
ferentiated from iPSCs. N-Butylidenephthalide (n-BP) is improvement [129].
derived from Angelica Sinensis. N-BP can reduce Aβ40
deposits, total tau protein, and its hyperphosphorylated CAR‑T
form in iPSCs-derived neurons induced by Down syn- CAR is a kind of engineering, which can enable lympho-
drome [114]. Graptopetalum paraguayense can improve cytes to identify and eliminate cells delivering homolo-
AD-related phenotypes, such as reducing Aβ 40, Aβ 42, gous target ligands. It has antigen binding domain, hinge,
and tau protein phosphorylation [115]. transmembrane domain and intracellular signal domain
iPSCs are differentiated into cardiomyocytes, which modules. By changing each component, its function and
are used in the research of related diseases. One study anti-tumour effect can be adjusted. At present, vari-
found that Salvia miltiorrhiza and Crataegus pentagyna ous types of CARs are being developed and designed to
have anti-arrhythmic effects. Salvia miltiorrhiza has an improve the safety and effectiveness in cancer treat-
antioxidant effect, regulates calcium treatment on myo- ment [130]. Clinically, treatment with CAR-T-cells first
cardial cells during I/R and decreases arrhythmia and requires T-cells, which can be obtained from the patient’s
apoptosis [116]. Crataegus pentagyna extract has an peripheral blood, or allogeneic CAR-T-cells obtained
anti-arrhythmic effect on cardiomyocytes derived from from a donor [131]. T-cells are stimulated and expanded
human arrhythmia-specific iPSCs [117]. In addition, Yix- in vitro and transduced with specific CAR genes through
inshu capsule has a protective effect on human iPSCs- viral vectors, and then, the CAR-T-cells are infused back
derived cardiomyocytes by reducing endothelin 1 (ET-1) into the patient to perform the set tumour-killing effect
induced contractile dysfunction, increasing brain natriu- in the patient’s body. This type of therapy is also called
retic peptide (BNP) content, and inducing morphological CAR-T-cell therapy (Fig. 3).
changes [118]. However, some plant extracts are toxic to In 2017, the FDA approved two types anti-CD19 CAR-
cardiomyocytes, such as liensinine and neferine [119], T-cell products to treat both B-cell ALL and diffuse large
mitragynine [120], and Erythrina senegalensis DC [121]. B-cell lymphoma, and these products have transformed
the field of anticancer immunotherapy [134]. However,
The effect of plant extracts on other stem cells there are still some limitations in CAR-T-cell therapy.
Ultraviolet-B (UVB) irradiation can damage the epider- Mechanisms hampering CAR-T-cell efficiency include
mis. Andrographis paniculata [122] promotes the prolif- limited T-cell persistence and therapy-related toxicity.
eration of epidermal stem cells (EpSCs) and anti-aging via Furthermore, severe toxicities, restricted trafficking to,
increasing integrin β1 and VEGF expression. Morin [123] infiltration into and activation within tumours, antigen
and Vanillin [124] significantly inhibited UVB-induced escape and heterogeneity; manufacturing issues; physical
Li et al. Stem Cell Research & Therapy (2022) 13:472 Page 8 of 14

Fig. 3 CAR-T-cell therapy and the four generations of improvements. The first-generation CARs were fused with a single-chain variable fragment
(scFv) to a transmembrane domain and an intracellular signalling unit: the CD3 zeta chain. Then, the second-generation CARs improved the
costimulatory molecule receptor-like CD28, which is the most commonly used. The second-generation CARs increased the production of cytokines
and enhanced durability. The third-generation of CARs design in-corporated an additional costimulatory domain to enhance CAR function and
included the scFv, the initial CD3ζ-chain, and the CD28 and 4-1BB or OX40 costimulatory domains [132]. At present, fourth-generation CAR-T
therapy has been extended. In this type of CAR-T-cell therapy, cytokine genes have been added to the structure, which can stimulate high cytokines
expression that enhances the activity of T-cells after CAR-T-cells are activated, thereby improving the antitumour activity of CAR-T-cells [133]

properties; and the immunosuppressive capacities of [159], Lycium barbarum [160], Ganoderma lucidum
solid tumours have prevented the success of CAR-T- [161], Yunzhi-Danshen [162] can upregulate ­ CD3+,
+ +
cells in these entities [135, 136]. Additionally, it may not ­CD4 , CD4 + /CD8 + and ­NK cells. Moreover, gastro-
be possible to obtain a sufficient number of T-cells from din was found to ameliorated the ­CD8+ T-cell-mediated
the patient because the patient is usually not considered immune response and significantly improved protection
for CAR-T-cell therapy, usually due to a reduction in the in tumour-challenged animals. This finding indicates that
number of original lymphocytes caused by previous cyto- gastrodin is a potential adjuvant contributing to antican-
toxic treatment [134]. In application, almost all CAR-T- cer immunomodulation.
cell products are derived from ­CD4+ T-cells and ­CD8+ On the other hand, the tumour microenvironment
T-cells, both cell populations likely contribute to treat- is a complex pathological system composed of tumour
ment effect [134]. Some plant extracts have beneficial cells, blood/lymphatic vessels, tumour stroma, and
effects on ­CD4+ T-cells and C ­ D8+ T-cells. For example, tumour-infiltrating myeloid precursors, providing a liv-
Fuzheng Qingjie [137, 138], Fuzheng Fangai [139], Xiaoji ing environment for tumour cells and promoting tumour
[13], Cistanche deserticola [140], Epimedium koreanum metastasis. In the tumour microenvironment, tumour-
Nakai [141], Glycyrrhiza uralensis [142, 143], Aidi [144], infiltrating myeloid precursors mainly include tumour-
and Scolopendra subspinipes [145–147] can increase in associated macrophages, tumour-associated dendritic
­CD4+ cells and the CD4/CD8 ratio, and produce FN-g, cells, and myeloid-derived suppressor cells, which inhibit
IL-2, IL-4, IL-6, and IL-7; Xiao Ai Ping [148], Lycium T-cells or other immune cells and play an important
barbarum [149–151], Dangguibuxue tang [152], Olden- role in its antitumour activity. Therefore, improving the
landia diffusa [153–155], Carthamus tinctorius [156], tumour microenvironment by targeting these cells is an
lectin-55 [157], and Tricosanthes kirilow [158] have an effective way to assist CAR-T-cell therapy. Liu J et al.
effect on increasing in ­CD8+ cells, and tumour infiltra- reviewed Chinese herbal medicine and its components
tion and increasing IFN-g and IL-10. Shenqi Fuzheng that induce tumour cell apoptosis and directly inhibit
Li et al. Stem Cell Research & Therapy (2022) 13:472 Page 9 of 14

tumour growth and invasion, providing new research present, cell therapy is promising. However, to under-
ideas for cell therapy [163]. stand the long-term effects, more in-depth research on
the dose and side effects of plant extract applications is
TCR‑T still needed. Although plant extracts are recognized as
Due to the limitations of CAR in the application, it only excellent alternatives to synthetic interventions, clini-
recognizes cell surface protein antigens, while TCR can cal application is challenging due to the variability and
distinguish intracellular proteins expressed as peptides complexity of the bioactive components present in the
on MHC class I molecules. Therefore, TCR-T therapy extracts, as well as the effects of solvents during extrac-
has superiority in the field of solid tumour treatment. tion. Therefore, the effects of plant extracts on cell ther-
The TCR can be produced in two ways. One method is to apy need to be better and more deeply researched to
identify and clone T- cells from patients with antitumour supplement the current deficiencies in cell therapy.
reactions. Their TCRs are inserted into retroviruses or
lentiviruses to infect target T-cells. Another method is Abbreviations
to isolate TCRs from humanized mice that recognize MSCs: Mesenchymal stem cells; NSCs: Nerve stem cells; CAR-T: Chimeric
tumour antigens. TCRs can be immunized with appro- antigen receptor T-cell immunotherapy; TCR-T: T-cell receptor modified T-cell
immunotherapy; ASCs: Adipose-derived stem cells; iPSCs: Induced pluripotent
priate tumour antigens because they can express human stem cells; ESCs: Embryonic stem cells; HLA-DR: Human leukocyte antigen-
MHC class I or II. After T-cells were isolated, the TCR antigen D related; BM-hMSCs: Bone marrow-derived human MSCs; ERK:
gene was cloned into a recombinant vector for genetic Extracellular signal-regulated kinase; Runx2: Runt-related transcription factor
2; HGPS: Hutchinson–Gilford progeria syndrome; VEGF: Vascular endothelial
engineering transformation of patients’ autologous growth factor; VEGFR: Vascular endothelium growth factor receptor; TCM:
T-cells [164]. Traditional Chinese medicine; ALP: Alkaline phosphatase; PPARγ: Peroxi-
Although effective responses have been observed in some proliferator activated receptor γ; BSNXD: BuShenNingXin decoction;
WS-MSCs: Wharton’s jelly-derived MSCs; C/EBP-α: CCAAT enhancer-binding
TCR-T-cell therapy, adverse reactions have become a protein-α; Smo: Smoothened; OGD: Oxygen and glucose deprivation; bFGF:
thorny issue in many trials. Most of the reasons are that Basic fibroblast growth factor; NSPC: Neural stem/progenitor cells; GFAP: Glial
TCR-T- cells, in addition to their killing effect on tumour fibrillary acidic protein; n-BP: Butylidenephthalide; ET-1: Endothelin 1; BNP:
Brain natriuretic peptide; UVB: Ultraviolet-B; EpSCs: Epidermal stem cells; ACT​
cells, severely destroy normal cells with the same antigen : Adoptive cell therapy.
[129]. Since TCR-T-cells have only emerged in recent
years, there are almost no plant extracts currently used Supplementary Information
in TCR-T-cell research. Parvifoline AA is an ent-kaurane The online version contains supplementary material available at https://​doi.​
diterpenoid and can significantly stimulate the level of org/​10.​1186/​s13287-​022-​03152-z.
NKG2D ligands on hepatocellular carcinoma cells, evi-
dently enhancing their recognition and lysis by NK cells Additional file 1: Table S1. Plant Extracts for the Osteogenesis of MSCs.
[14]. Perhaps improving the efficacy of TCR-T-cells in the
immunosuppressive microenvironment and determining Acknowledgements
that the expression is mainly (if not completely) limited We thank Lei Tong for guidance in drawing from University of science and
technology Beijing.
to cancer cell targets may be a future research direction
for plant extracts. Author contributions
H.J Yang, X.Y. Li and P. Chen designed the idea of this review; C.F. Li, Zh. Cui,
S.W. Deng and P. Chen co-wrote the paper with input from all authors. All
Conclusion authors read and approved the final manuscript.
Plant extracts are relatively easy to obtain and have
Funding
significant activity in the treatment of many diseases. This study was supported by fundamental Research Funds for the Central pub-
The above review shows that plant extracts have an lic welfare research institutes of China (ZZ13-YQ-082-C1; JBGS2021001), the
effect on stem cell proliferation or directed differenti- Scientific and Technological Innovation Project of China Academy of Chinese
Medical Sciences (CI2021A00610).
ation and play an important role in solving the prob-
lem of insufficient endogenous stem cells and directed Availability of data and materials
differentiation of stem cells; In immune cell therapy, Not applicable.
the effect of plant extracts on stem cells are reflected
in the beneficial effects on C ­ D4+ T-cells and C ­ D8+ Declarations
T-cells and the improvement of the tumour microen- Ethics approval and consent to participate
vironment. Moreover, plant extracts, such as astra- Not applicable.
galoside [165], paeoniflorin [166], and licorice [167],
Consent for publication
have a good immunoregulatory and anti-inflammatory Not applicable.
activities and may provide a better treatment plan for
the cytokine storm caused by cell therapy [168]. At
Li et al. Stem Cell Research & Therapy (2022) 13:472 Page 10 of 14

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