History of Regenerative Medicine Looking Backwards to Move Forwards(Review) Kemp P
World J Stem Cells. 2020 Jun 26; 12(half dozen): 488–499.
Strategies for treating oesophageal diseases with stalk cells
Yang Gao
Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang Province, China
Shi-Zhu Jin
Department of Gastroenterology and Hepatology, The Second Affiliated Infirmary of Harbin Medical University, Harbin 150086, Heilongjiang Province, Mainland china. nc.ude.umbrh@nijuhzihsrd
Received 2020 Feb xiv; Revised 2020 May 2; Accepted 2020 May nineteen.
Abstract
There is a broad range of oesophageal diseases, the most general of which are inflammation, injury and tumours, and treatment methods are constantly existence developed and updated. With an increasingly comprehensive agreement of stem cells and their characteristics of multilineage differentiation, self-renewal and homing as well as the combination of stem cells with regenerative medicine, tissue applied science and gene therapy, stalk cells are playing an important role in the treatment of a diverseness of diseases. Mesenchymal stem cells have many advantages and are most commonly applied; however, most of these applications have been in experimental studies, with few related clinical trials for comparison. Therefore, the methods, positive significance and limitations of stem cells in the handling of oesophageal diseases remain incompletely understood. Thus, the purpose of this paper is to review the current literature and summarize the efficacy of stem cells in the treatment of oesophageal diseases, including oesophageal ulceration, acute radiation-induced oesophageal injury, corrosive oesophageal injury, oesophageal stricture germination afterwards endoscopic submucosal autopsy and oesophageal reconstruction, likewise equally factor therapy for oesophageal cancer.
Keywords: Stem cells, Oesophageal diseases, Differentiative capacity, Regenerative medicine, Tissue engineering, Gene therapy
Core tip: Stem cells accept many characteristics and can be used to treat various diseases. Currently, the employ of stem cells for the treatment of oesophageal diseases is developing but is notwithstanding non very common. Therefore, this paper summarizes the relevant literature on stem prison cell therapy for oesophageal diseases, including oesophageal ulceration, astute radiation-induced oesophageal injury, corrosive oesophageal injury, oesophageal stricture formation afterwards endoscopic submucosal dissection and oesophageal reconstruction, also equally gene therapy for oesophageal cancer, to promote better the development of stem cell therapy for oesophageal diseases.
INTRODUCTION
At that place are a wide variety of oesophageal diseases, including mainly inflammation, tumours and injury. Treatment methods include drugs, endoscopic treatment and surgery[1]. With the development of stem prison cell-related research and applied science, stalk cells have gained increasing attention in the context of treating various diseases[2].
By definition, stem cells accept the capacity for multilineage differentiation and cocky-renewal. They can differentiate into many specific types of cells in vivo[iii]. Stem cells tin divide into totipotent, pluripotent, multipotent and unipotent stem cells according to their differentiation potential. Totipotent stalk cells can differentiate into any kind of cells, and pluripotent stalk cells can differentiate into cells of all three germ layers. Pluripotent stem cells can differentiate into many kinds of cells, but they may not embrace all cells of i germ layer, and unipotent cells tin can simply differentiate into ane type of cell[4-half-dozen]. Stem cells can be divided into embryonic stem cells and developed stem cells according to their source. Embryonic stem cells at the morula stage, which are a kind of totipotent stem cells, take the differentiation potential to form a complete private. With embryonic growth, the potential of stalk cells continues to refuse from totipotency to pluripotency[7]. Developed stalk cells are undifferentiated cells existing in a kind of differentiated tissue that can self-renew and specialize to course cells that make upwards this type of tissue. Developed stem cells can include pluripotent stalk cells and unipotent stem cells[half-dozen]. For instance, haematopoietic stem cells are the most feature pluripotent stem cells and can differentiate into at to the lowest degree 12 kinds of blood cells[8]. Mesenchymal stem cells (MSCs) tin can differentiate into a variety of mesodermal cells (such as bone, cartilage, muscle, and fat cells) and other blastodermal cells (such every bit neurons)[9].
Currently, MSCs are studied the most intensely and used the near widely. MSCs are relatively abundant and piece of cake to isolate and culture. The main sources include adult bone marrow, umbilical cord or placental blood and adipose tissue, the latter of which is being increasingly developed and used every bit a source[10]. MSCs tin can also be isolated from the periosteum, skeletal muscle, teeth and other tissues[11,12]. Isolated MSCs can be used to care for tissue and organ impairment and functional failure. MSCs have a powerful proliferation ability and multidirectional differentiation potential and tin differentiate into osteoblasts, chondrocytes, adipocytes, liver cells, muscle cells, stromal cells and other cells under appropriate conditions in vivo or in vitro[xiii]. Stem cells can too be used as carriers for gene therapies. In detail, MSCs are the most widely used for this purpose. They tin can not but exist easily transfected with exogenous genes just can also express the protein of exogenous genes and retain their own phenotype later on the introduction of exogenous genes[fourteen]. This characteristic, combined with the multilineage differentiation potential of MSCs, renders MSCs potentially ideal target cells for gene therapy. MSCs have depression immunogenicity and can reduce the allowed exclusion outcome during cell transplantation[15]. Currently, stem cells tin can be cultured and isolated artificially in vitro according to certain purposes, and various cells, tissues and organs can be constructed using stalk cells as a source for transplantation. Stem cells also exhibit homing; that is, under the influence of many factors, stem cells will migrate in a directional manner[16]. It is widely believed that the mechanism is based on the release of some factors from the site of injury, which bind to receptors for these factors on the surface of stalk cells[17]. This characteristic allows stem cells to serve every bit a carrier of many therapeutic agents (Figure 1).
Sources and characteristics of mesenchymal stem cells. Mesenchymal stalk cells (MSCs) have a wide range of sources, including adult bone marrow, umbilical cord or placental blood, adipose tissue, skeletal muscle, teeth and other tissues. MSCs have the capacity for multilineage differentiation and self-renewal. They can differentiate into neurons, muscle cells, osteoblasts, chondrocytes, adipocytes, hepatocytes so on under appropriate weather condition. MSCs have the characteristic of homing, the mechanism of which is widely believed to be that sites of injury release various factors, and there are receptors for these factors on the surface of MSCs. MSCs have low immunogenicity and can be cultured and isolated artificially in vitro for transplantation. MSCs can also be used as carriers for cistron therapy. MSCs can exist transfected with therapeutic genes and limited the protein of exogenous genes well.
Stem cells can be effective in the handling of many diseases, such equally cardiovascular diseases, nervous system diseases, bone and cartilage diseases and inflammatory diseases. Nevertheless, stem cells are not commonly used in the handling of the oesophageal diseases. The mechanism of using stem cells for the treatment of some common diseases of the oesophagus tin exist like to that applied in the handling of other diseases. Based on the characteristics of the oesophagus itself, stem cells could play an even greater role. The post-obit describes the apply of stalk cells for the treatment of different oesophageal diseases (Table 1).
Table 1
Related stem prison cell transplantation experiments
| Stem cells sources | Transplant recipients | Transplant methods | Results | Ref. |
| Bone marrow cells from male human donors | Four female person homo recipients | Bone marrow transplantation | Regeneration of gastrointestinal epithelia | [22] |
| High K19-expressing MSCs from bone marrow of mice | Mice, H. felis infected mice | Gastric wall injection, blastocyst injection | Contributed to gastric epithelial regeneration and repair. | [23] |
| MSCs from bone marrow of male rats | Female person rats with gastric ulcers | Gastric wall injection surrounding the ulcer | Acceleration of gastric ulcer healing | [24] |
| MSC sheets from inguinal fat tissue of rabbits | Rabbits with oral mucosal ulcers | MSC sheets transplanted onto mucosal ulceration | Full-thickness mucosal healing and complete basal cell coverage | [26] |
| Bone marrow cells from mice | Mice with radiation-induced oesophageal injury | Intravenous injection | Repopulation of the irradiated oesophageal squamous epithelium | [32] |
| DPSCs from rats | Rats with acute radiation-induced oesophageal injury | Intravenous injection (tail vein) | Healing of tissue damage and improvement the oesophageal function | [34] |
| MSCs from bone marrow of rats | Rats with oesophageal lye burn | Intravenous injection (tail vein) | Differentiation to epithelial and muscle cells | [37] |
| Double-layered ADSC sheets from the abdominal subcutaneous fat of pigs | Pigs treated with hemi-circumferential ESD | ADSC sheets placed on the wound site with endoscope | Reduced caste of oesophageal stricture and fibrosis development | [47] |
| CM of AMSCs from the foetal membrane of significant women | Pig treated with semi-circumferential ESD | CM gel applied on the wound site with endoscope | Reduced oesophageal fibrosis and inflammation | [48] |
| MSCs from bone marrow of pigs | Pigs for circumferential replacement of oesophagus | MSC-seeded matrix for circumferential Replacement of oesophagus | Dispatch of epithelial and muscle prison cell regeneration | [56] |
| MSCs from bone marrow of rats | Rats for circumferential replacement of oesophagus | MSC-seeded decellularized oesophagus for orthotopic replacement | Regeneration of functional epithelium, muscle fibres, nerves and vasculature | [57] |
| MSCs from adipose tissue of pigs | Pigs for full thickness circumferential resection of oesophagus | MSC-seeded synthetic grafts implanted into oesophagus | Regrowth of mucosa, submucosa, and smooth muscle layers and blood vessels | [59] |
| MSCs from bone marrow of human donors | Rats for interposition procedure betwixt the oesophagus and stomach | MSCs and other cells constructing multicellular bogus oesophagus with bio-3D printing transplanted into oesophagus and tum | Full coverage of inner luminal surface by epithelial cells | [60] |
| MSCs from bone marrow of human donors, then MSCs transduced with IFN-β gene | Rats inoculated with melanoma cells and MSCs | Intravenous injection (tail vein) | Proliferation of MSCs in tumours and inhibition of malignant cell growth | [66] |
| MSCs transduced with IFN-α gene | Mice inoculated with melanoma cells | Intramuscular injection | Decrease in tumour cell proliferation and consecration of neoplasm cell apoptosis | [67] |
| MSCs from bone marrow of human donors, then MSCs transduced with IFN-λ gene | Mice injected with H460 cancer cells | Subcutaneous injection | Induction of tissue necrosis and inhibition of neoplasm cell growth in lung metastases | [lxx] |
| MSCs from bone marrow of man donors, then MSCs modified with TRAIL gene | Mice injected with Eca-109 cancer cells | Directly injection into tumour | Induction of Eca-109 oesophageal cancer prison cell apoptosis | [72] |
| MSCs from bone marrow of rats, then MSCs transfected with TRAIL gene | Mice injected with B16F10 cancer cells | Intravenous injection (tail vein) | Reduction of lung metastases and induction of neoplasm cell apoptosis | [62] |
| MSCs from adipose tissue of human donors, and then MSCs transfected with TRAIL gene | Mice injected with HeLa cells | Flank injection, tumour injection | Inhibition of tumour cell growth | [73] |
OESOPHAGEAL ULCERATION
Oesophageal ulcers are by and large caused past gastrointestinal reflux illness[18]. The incidence of gastroesophageal reflux disease has increased significantly in the by decade[19]. An ulcer is a defect in the mucosa that can deeply penetrate or even perforate the muscle layer. It is generally caused by ischaemia, oxygen radical germination or nutritional transport blockage. Ulcer tissue accumulates a variety of cytokines released past immune cells that play a complex function in diverse stages of ulcer recovery, including cell proliferation, re-epithelialization, neovascularization and scar germination. The natural recovery of ulcers consists of the evolution of surrounding cells towards the centre of the ulcer site and reconstruction of the mucosa. However, developed stem cells derived from bone marrow accept the ability to differentiate into mature epithelium, which can make full the ulcer area with epithelium and advance the procedure of re-epithelialization[20,21].
Okamoto et al[22] transplanted bone marrow cells from male donors into four female patients who needed transplantation treatment due to haematological diseases. Epithelial tissue biopsy samples were nerveless from the recipient's digestive tract through gastroenteroscopy. With immunohistochemistry and fluorescence in situ hybridization, information technology could be determined that at that place were donor-derived cells in the recipient's epithelial tissue, most of which were epithelial cells and not inflammatory cells[22]. Okumura et al[23] demonstrated that MSCs in os marrow tin play a part in mucosal re-epithelialization and repair.
Cytokeratins are a grade of proteins that maintain the cellular structure of epithelial cells. Keratin 19 (K19) is a cytokeratin and tin be considered a marker of epithelial cells. Therefore, K19 can be used to identify the transformation of MSCs into epithelial cells. Okumura et al[23] isolated and cultured MSCs with high K19 expression and injected them direct into the gastric wall of mice. Later 24 h, MSCs were found to accept filled the gastric mucosa. After 4 wk, the expression of specific markers of epithelial cells was found at the site of MSC injection[23]. Hayashi et al[24] injected rat MSCs into the tummy wall of rats, observed the recovery of gastric ulcers induced by acetic acid and detected the expression of vascular endothelial growth factor (VEGF) produced by the transplanted MSCs in the rats. VEGF is a kind of angiogenesis regulatory factor that can induce the formation of new blood vessels in granulation tissue and is of neat significance for ulcer healing[25]. The application of VEGF antibody can inhibit the therapeutic upshot of MSCs on ulcers in a dose-dependent manner[24]. Therefore, VEGF plays a meaning role in promoting angiogenesis in the treatment of ulcers with MSCs. The mechanisms of gastric ulceration and oesophageal ulceration are similar, so the above experimental principle is too applicable to the oesophagus.
Compared with bone marrow-derived stem cells, adipose-derived stem cells (ASCs) are easier and less invasive to obtain and easier to isolate and culture. 1 report demonstrated that the use of ASC sheets accelerated the healing of oral mucosal ulcers[26]. In many ischaemic models, ASCs have been shown to increase the capillary density and decrease the inflammatory response[27]. ASCs can secrete paracrine factors that promote tissue healing[28], and their differentiation potential is also conducive to the treatment of damaged tissues[29].
ACUTE Radiation-INDUCED OESOPHAGEAL INJURY
Radiation therapy for various cancers in the chest, peculiarly lung cancer, will inevitably pb to radiation-induced oesophageal injury[30]. Even so, the occurrence of radiations-induced oesophagitis will hinder the handling of cancer, and there are very few drugs that can protect the oesophagus from radiation[31]. Therefore, stem cell therapy constitutes an innovative and effective handling strategy.
Epperly et al[32] simulated a model of radiation-induced oesophageal injury with 30 Gy of radiations. After bone marrow cells were injected intravenously into the model mice, the cells migrated to the oesophageal lesions, differentiated into oesophageal squamous epithelial cells and improved the overall survival rate of the mice. In addition, dental pulp stalk cells (DPSCs) are a blazon of MSC that are used to repair periodontal tissues. In fact, in improver to forming odontoblasts, they tin as well differentiate into adipose, bone, cartilage, muscle, vascular endothelial, liver and nervus cells, among others, through induction with different cytokines. The isolation and drove of DPSCs is highly not-invasive and inexpensive[33]. Zhang et al[34] placed iodine 125 (I125) particles into a disposable ureteral lumen and introduced them into the oesophagus to create an astute radiation-induced oesophageal injury model. DPSCs cultured in vitro were injected into the experimental Sprague Dawley rats through the tail vein. Finally, it was demonstrated that DPSC transplantation was helpful for the treatment of astute radiation-induced oesophageal injury. DPSCs expanded in vitro can abode to oesophageal lesions to proliferate and trans-differentiate into oesophageal stalk cells[34].
CORROSIVE OESOPHAGEAL INJURY
Corrosive oesophageal injury occurs rarely in adults as an accident, but it is very common amid children due to the characteristics of the children themselves, especially in many developing countries, for which in that location are many social causes[35]. The mucosal layer of the oesophagus is destroyed when it is exposed to corrosive substances. As the illness progresses, the harm invades the muscular layer. In severe cases, perforation occurs. Self-repair may eventually pb to fibrosis, stenosis and shortening of the oesophagus[36]. Drugs tin can exist effective to varying degrees, but they cannot pb to much improvement in cases of serious injury.
To test the application of stalk cells, Kantarcioglu et al[37] fabricated a standard model of oesophageal caustic injury with lye in 65 Wistar rats. Bone marrow MSCs were obtained from the tibia and femur of rats and cultured in vitro. They were injected into the experimental rats through the tail vein. Finally, a histopathological evaluation was performed, including conclusion of submucosal collagen, mucosal muscle injury, intrinsic musculus injury and collagen degradation as well as calculation of the oesophageal stenosis index. Positron-emission tomography was used to notice the homing behaviour of the stalk cells. The results showed that the structure of the oesophagus was not completely restored, merely the stem cells indeed showed homing and differentiation behaviour. The researchers speculated that the less than ideal treatment may be related to the number and location of stalk jail cell injections[37]. Bone marrow MSCs accept the ability to abode to damaged tissue and differentiate into various cell types. Pittenger et al[13] and Okamoto et al[22] proved that MSCs can differentiate into epithelial cells in the damaged gastrointestinal tract to promote repair. Oswald et al[38] demonstrated experimentally that os marrow MSCs can differentiate into endothelial cells in vitro, greatly promoting angiogenesis and therefore facilitating tissue repair.
OESOPHAGEAL STRICTURE FORMATION Later on ENDOSCOPIC SUBMUCOSAL Autopsy
With the increasing number of patients with oesophageal cancer, endoscopic submucosal dissection (ESD) has get a mature handling strategy, specially for early oesophageal cancer[39,40]. Notwithstanding, ESD has many side effects, and the incidence of stricture formation due to the peeled mucosa is very high, especially when more than three-quarters of the oesophagus is stripped. Safe endoscopic balloon dilatation and steroid hormones take traditionally been constructive strategies for preventing oesophageal stricture germination, although these methods can crusade discomfort and complications[41]. Regenerative medicine has been widely recognized as a method of treating diseases using the body'southward own components[42]. Due to the development of regenerative medicine, techniques using autologous epidermal cell sail transplantation have been adult to treat stenosis[43]. This applied science preserves the adhesion molecules between cells so that the cells can remain linked together during transplantation and adhere to damaged tissue[44]. For example, cell sheets equanimous of oral mucosal cells can promote oesophageal epithelial regeneration after ESD[45].
Adipose-derived stromal cells (ADSCs) are a type of adult stem cell that tin can differentiate into unlike types of cells and exert paracrine and angiogenic effects to facilitate tissue repair[46]. In addition, ADSCs are like shooting fish in a barrel to isolate. Perrod et al[47] performed ADSC canvass transplantation into the oesophagus post-operatively. Compared with the control, ADSC transplantation reduced the incidence of severe stenosis iii d postal service-operatively. In addition to stem cells themselves, various secretory factors produced during stem cell differentiation may also have positive effects. Mizushima et al[48] speculated that the therapeutic outcome of foetal membrane or amniotic MSC (AMSC) transplantation on diverse diseases may be attributed to the factors secreted by the AMSCs; thus, conditioned medium (CM) obtained from AMSCs was used to explore its therapeutic effect on post-ESD stenosis. The researchers isolated and cultured AMSCs from the foetal membrane during caesarean section in meaning women who had provided consent and used them to set up CM gel. The experiment utilized different gradients and frequencies of CM gel usage to compare the use of steroid drugs. The degree of oesophageal stenosis was assessed past computing the lateral mucosal constriction rate and performing histological and immunohistochemical examinations. The results demonstrated that CM could reduce fibrosis and inflammation in the oesophagus after surgery[48].
OESOPHAGEAL RECONSTRUCTION
Oesophageal replacement or resection is required in many diseases, such as long-gap oesophageal atresia, a congenital disease in children, and oesophageal cancer in adults that requires oesophagectomy. Traditionally, oesophageal tissue is often replaced by tissue from the tummy, jejunum and colon. Many post-operative complications, such every bit stenosis, reflux, delayed emptying, anastomotic fistula and dysfunction, are inevitable and reduce the quality of life to a large extent[49-51]. On the basis of regenerative medicine technologies, the rise of tissue engineering has greatly improved the treatment of this kind of disease. Tissue engineering integrates technology and life science and uses scaffolds or a combination of scaffolds and cells to reconstruct the structure or role of tissues or organs[52]. Scaffolds can exist acellular or seeded with cells. However, the transplantation of acellular scaffolds requires advanced materials, which are needed to support the regeneration of respective tissues, such as epithelium and musculus. In oesophageal applications, it is possible to seed epithelial cells on the scaffold in accelerate, which is helpful for epithelialization of the oesophagus, just the muscular layer is difficult to form[53]. Although many experiments accept successfully transplanted autologous smooth muscle cells into the oesophagus, their proliferation capacity is limited[54].
Zani et al[55] have suggested that stem cells can assist with oesophageal regeneration. In a study past Catry et al[56], MSCs promoted the therapeutic effect. They isolated MSCs from the posterior iliac crest by aspiration and cultured them in vitro; then, they compared the outcome of a stalk cell-seeded matrix with that of a not–stem prison cell-seeded matrix in full-layer oesophageal replacement. The results showed more epithelial cells in the early stage in the transplanted surface area of the oesophagus forth with muscle prison cell regeneration in the experimental group with stem cells than in the control grouping without stem cells. Therefore, under the effect of stem cells, the process of epithelial and muscle cell regeneration volition be accelerated[56]. Sjöqvist et al[57] successfully integrated bone marrow MSCs into acellular scaffolds to replace the oesophagus and proved that MSCs can differentiate into oesophageal-related cells. There has at present been a clinical example of using tissue technology to treat an oesophageal defect. The patient underwent commercial stent placement only did not recover as expected. The researchers used extracellular matrix and autologous plasma to assist repair the oesophagus. The extracellular matrix can provide an environment for stem jail cell differentiation and attract and induce stem cells to promote organogenesis. When the stent was removed, endoscopic ultrasonography showed that the newly formed oesophageal wall contained the 5 normal structural layers. Furthermore, the new oesophagus also accomplished a certain degree of functional recovery[58].
In add-on to MSCs, ASCs are easy to obtain and abundant in number and tin can play an important role in tissue applied science of the oesophagus. According to experiments in which ASCs successfully differentiated into polish muscle cells, Wang et al[54] implanted ASCs into the muscle layer of an acellular matrix, and the results showed that the ASCs fastened to the muscle layer and achieved migration and proliferation. La Francesca et al[59] placed scaffolds loaded with adipose-derived MSCs into a pig model of oesophagectomy, forth with a concrete stent supporting the oesophageal construction. Histological examination of the oesophagus and an evaluation of oesophageal stenosis were performed. Afterwards removal of the physical stent and scaffold, the formation of oesophageal mucosa and muscularis was observed, equally was vascularization, and there was no oesophageal stricture formation[59]. Currently, on the basis of tissue applied science technology, it is possible to utilise scaffold-free structures equanimous of a diversity of cells to replace the oesophagus using biological 3D press technology. In jail cell mixtures, the more MSCs, the better the construction and function of the oesophagus[sixty].
GENE THERAPY FOR OESOPHAGEAL CANCER
Oesophageal cancer ranks fifth among the about common cancers in China. Worldwide, 60% of new cases of oesophageal cancer occur in China[61]. Based on traditional treatment with surgery, radiotherapy and chemotherapy, gene therapy, which has been successfully practical in the treatment of many diseases, has been developed for oesophageal cancer. The office of the therapeutic gene depends on the efficacy of the delivery carrier, and effective delivery to the tumour site is key in gene therapy. Viral vectors were more unremarkably used in the past, simply at that place were some side effects that could pb to systemic impairment, and many new vectors accept express therapeutic effects due to their respective characteristics[62]. MSCs can even so maintain their original characteristics after being successfully transfected with exogenous genes and cultured in vitro. MSCs can successfully express exogenous gene products in vitro and secrete therapeutic proteins equally carriers in vivo[63]. MSCs have been proven to inhibit tumour prison cell proliferation and tumour angiogenesis by secreting soluble factors in vitro[64]. In that location are higher levels of paracrine growth factors in tumour tissues than in normal tissues. The proliferation of MSCs requires the presence of these factors[63]. Hu et al[62] plant that stromal cell-derived gene i may attract MSCs to migrate to the neoplasm microenvironment in vitro. Therefore, MSCs, being able to migrate to tumour tissues, are too considered to be skillful carriers for therapeutic genes and anti-tumour biological agents[65].
Studeny et al[66] investigated the consequence of MSCs transfected with the interferon β (IFN-β) factor on tumour tissue. Clinical trials have shown that the use of IFN is limited by the systemic maximum tolerable dose and cannot fully exert its anti-tumour effect. However, MSCs transfected with the IFN-β gene can preferentially localize to tumour tissues and then that IFN-β is locally released and minimally affects other areas[66]. MSCs with the IFN-α cistron tin can regulate the activeness of immune cells by secreting IFN-α in tumour tissue[67]. IFN-λ tin can inhibit cancer prison cell proliferation by blocking the G1 phase of oesophageal cancer cells[68]. Li et al[69] found that adenovirus carrying the IFN-λ factor can induce mitochondrial-mediated oesophageal cancer cell apoptosis in mice. Therefore, information technology is a feasible method to introduce the IFN-λ gene into stem cells to treat oesophageal cancer. Yang et al[70] verified that IFN-λ-modified MSCs inhibit the growth of tumour cells by activating the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) molecular pathway. TRAIL is a molecule that tin induce the apoptosis of tumour cells, simply its brusk half-life in plasma limits its wide awarding[71]. Li et al[72] introduced the TRAIL factor into human being bone marrow-derived MSCs by adenovirus vector and delivered the MSCs into mice by subcutaneous injection on the back. The results showed that the MSCs could induce the apoptosis of oesophageal neoplasm cells and inhibit the growth of tumour tissue through the expression of TRAIL. Non-viral vectors can also exist used to transfect MSCs, which would take no viral interference with the treatment and could improve the targeting consequence of MSCs[62]. Human adipose-derived MSCs are also an effective tool for TRAIL gene therapy for cancer, and the material source is more advantageous[73].
In that location are many other tumour-suppressing genes that tin can exist introduced into MSCs for cancer treatment, such equally IL-12, IL-24 and pigment epithelium-derived factor. Yet, few genes have been identified for treating oesophageal cancer, and these tin can be further developed in the future[74-76]. In that location is some debate regarding the effect of stem cells on tumours. Some experiments have shown that MSCs tin promote tumour growth, which may be due to different experimental designs, the immunosuppressive effect of stem cells themselves or some cytokines secreted by stem cells[10].
PROSPECTS
There are still some areas that demand to be developed and expanded in the handling of oesophageal diseases. For instance, stalk cells tin be used as factor carriers or drug carriers straight, and drugs tin can be released in a targeted style depending on the function of stalk prison cell homing. The combination of nanocarriers and MSCs volition let meliorate control over the position and mode of drug release[77]. Additionally, MSC-derived extracellular vesicles (EVs) take practiced prospects in regenerative medicine techniques[78]. As phospholipid bilayer vesicles, EVs secreted past MSCs contain many substances, such as enzymes, indicate molecules and RNA. There have been many experiments showing that the EVs of MSCs tin can alleviate or care for many diseases by transmitting the effects of MSCs, including inhibiting the inflammatory response, promoting cell proliferation and promoting angiogenesis and anti-apoptosis ability. Future strategies could include increasing the content of active molecules in EVs, targeting them to damaged tissues, evading the clearance system to improve the action fourth dimension and using EVs for drug delivery to improve the therapeutic efficiency[79]. However, there is still much to larn about stem cells. In standing to explore the benefits of stalk cells for treating disease, there are still many uncertain factors and possible risks. In a model of oesophagitis and intestinal metaplasia in female experimental rats, os marrow stalk cells from male rats were injected into the tail vein of the experimental rats. The Y chromosome from the male rat cells could be plant in the oesophageal squamous epithelium and metaplasia columnar epithelial cells in the female experimental rats, although the possibility of cell fusion could not exist ruled out. Nevertheless, summarizing like experimental studies, information technology is undeniable that stem cells tin can promote the germination of oesophageal epithelialization and oesophageal metaplasia. It is well known that oesophageal metaplasia is an important procedure in the formation of Barrett'due south oesophagus, and Barrett's oesophagus is a risk gene for oesophageal cancer[eighty]. In improver, genetically modified MSCs can exist used to care for tumours. However, information technology is controversial whether bone marrow MSCs inhibit or promote tumour tissue activity. Experiments take shown that bone marrow MSCs can inhibit tumour jail cell proliferation and promote neoplasm cell apoptosis in vitro simply can promote neoplasm growth in vivo, which may exist related to the promotion of tumour angiogenesis[81].
Conclusion
In summary, the treatment of oesophageal diseases by stalk cells can be based non only on their own characteristics, such as multilineage differentiation, self-renewal, depression immunogenicity and homing capacity, for the recovery and reconstruction of oesophageal structure and function to a certain extent, but also on integration with other biotechnology, the combination of which has greater therapeutic efficacy than either component solitary. Although there take been few clinical trials, the prospects of stalk cells in the treatment of oesophageal diseases are very promising. In addition, the function of stem cells has not still been completely understood. In the process of stem jail cell evolution, there are even so many unknown and uncertain factors to exist explored.
Footnotes
Conflict-of-interest statement: There is no conflict of interest associated with any of the senior author or other coauthors contributed their efforts in this manuscript.
Manuscript source: Invited manuscript
Peer-review started: February fourteen, 2020
Commencement decision: April 29, 2020
Article in press: May 19, 2020
Specialty type: Prison cell and tissue engineering science
Land/Territory of origin: Communist china
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P-Reviewer: Ullah M S-Editor: Yan JP 50-Editor: Filipodia Due east-Editor: Liu MY
Contributor Information
Yang Gao, Department of Gastroenterology and Hepatology, The 2nd Affiliated Infirmary of Harbin Medical University, Harbin 150086, Heilongjiang Province, China.
Shi-Zhu Jin, Department of Gastroenterology and Hepatology, The Second Affiliated Infirmary of Harbin Medical Academy, Harbin 150086, Heilongjiang Province, China. nc.ude.umbrh@nijuhzihsrd.
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