Stem cells: a new strategy for treatment of(5)

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摘要：[34] Spies C, Luetz A, Lachmann G, et of granulocyte-macrophage colony-stimulating factor or influenza vaccination on HLA-DR, infection and delirium days in immunosuppressed surgical patients:double b

[34] Spies C, Luetz A, Lachmann G, et of granulocyte-macrophage colony-stimulating factor or influenza vaccination on HLA-DR, infection and delirium days in immunosuppressed surgical patients:double blind, randomised controlled trial[J].PLoS One,2015, 10(12):e0.

[35] Nicolay NH, Lopez Perez R, Debus J, et stem cells—A new hope for radiotherapy-induced tissue damage?[J].Cancer Lett, 2015, 366(2):133-140.

[36] Huang HP, Chang MH, Chen YT, et elevation of hepatocyte growth factor activator inhibitors in cholangiopathies affects liver fi brosis and differentiation[J].Hepatology, 2012, 55(1):161-172.

The development of antibiotics has provided clinicians with the ability to kill major pathogens and cure infectious have saved the lives of many infected patients and provided significant control of many serious infectious , the widespread use of antibiotics has led to the induction of drug-resistant bacteria, such as methicillinresistant Staphylococcus aureus[1-2], penicillin-resistant Streptococcus pneumoniae[3-4], vancomycin-resistant Enterococci[5-6], Escherichia coli harboring mcr-1(a colistin-resistant gene)[7].There is now evidence for β-lactamases, extended-spectrum β-lactamases[8]and new delhi metallo-β-lactamase 1[9]in Klebsiella pneumoniae, Escherichia coli, and multidrug-resistant forms of Pseudomonas aeruginosa, Acinetobacter,Stenotrophomonas maltophilia[10-12], even extremely drug-resistant Mycobacterium tuberculosis[13-14]and other species[15].The evolution of multidrug-resistant bacteria has made standard anti-infection therapy more difficult[16-17].Thus, there appears to be a recrudescence of certain infectious diseases, such as tuberculosis[18-19]and malaria[20].Antimicrobial therapy cannot cure all infectious diseases[21].The most effective treatments are for bacteria,followed by fungi and parasites, and then particular, some antiviral drugs, such as lamivudine and adefovir, can only inhibit viral spread instead of actually killing viruses[22].Furthermore, the evolution of new variants of viruses presents an additional problem[23-24].When a new viral disease breaks out, no specific drugs can cure the disease or effectively prevent an has led to increased prevalence of several serious viral diseases while severe acute respiratory syndrome(SARS), human H7N9[24], Zika virus[25], Ebola virus[26],and Middle East respiratory syndrome coronavirus(MERS-CoV)[27]are the best known new antimicrobials continue to be developed, new ideas and treatment modalities are needed to prevent and cure infectious was accepted that our body could get some selfrepairing from impairments including infection, which was regarded as self-organization or autopoiesis[28].Until now, few researchers can launch their understandings on the primary forces for self-organization or autopoiesis in our body.In past, our researches had hypothesized that the self-organization in our body stemmed from the interrelationships between the stem cell proliferation and differentiation (SCPD) and the energy metabolism while the SCPD are the core of autopoiesis in our , abnormality of SCPD may be a new factor for the occurrence of infection while the stem cell will become another target for the treatment of infectious essential processes in the multicellular organismsWith the arrival of the 21st century, stem cell research has become an important new area of studies have examined the utilizations of stem cell transplantation for diverse clinical applications,such as leukemia[29], heart disease[30], liver disease[31],nervous system diseases[32], and other conditions[33].These applications not only provided new hopes for patients, but also implied that stem cell played an important role for the patient to get recovery from our novel viewpoint, the process of SCPD is one of the core physiological processes in multicellular organisms (Fig.1).Stem cells are undifferentiated cells with the capacity of infinite or long-term selfrenewal and the ability to develop into one or more types of specialized stem cells are classified as totipotent, multipotent or unipotent according to their potential for differentiation into different specialized cells.A multicellular adult is derived from a fertilized egg, which consists of totipotent stem cells that can develop into all of the different forms of somatic cells by proliferation and cells proliferate and the embryo develops into an adult, there is a gradual decrease in the differentiation capacity of cells, although a number of bone marrow stem cells remain in the mature human marrow stem cells are considered to be proliferation and differentiation, they can produce multipotent stem cells, then unipotent stem cells, and ultimately a variety of fully differentiated cells that participate in tissue self-renewal and , the stem cells in marrow are regarded as stem cell reservoir in our Schematic diagram of human growthNearly all researches were concerned on the exogenous factors and/or genes which had some effects on the SCPD.It should also be pointed out that the monosaccharides, amino acids, fatty acids and so on, are the basic materials for the basic materials play two essential roles in the SCPD: fi rstly, the oxidation of these materials affords energy for the behaviors of the stem cells including cell division; secondly, these materials can be used to synthesize biomacromolecules such as glycoproteins, lipoproteins, DNA, RNA and so on for constructing the architectures of cells, and the sufficient accumulation of these biomacromolecules will advantage the stem cells to go on the way of proliferation and our body, all the basic materials for SCPD are derived from being taken, foods will be digested into monosaccharides, amino acids, fatty acids, glycerol, and other small molecules for absorption in gut; and the waste products will be removed from the , there are two basic processes in the metabolism of food after being , after absorption, small molecules (monosaccharides, amino acids, fatty acids, and glycerol) are oxidized into water,carbon dioxide, nitrogen-containing organic products,and other small water-soluble this process, the released energy will be used to drive diverse physiological functions, and these processes should also be regarded as the energy metabolisms in our , monosaccharides, amino acids, fatty acids, and glycerol should also be regarded as sources of high energy , these high energy molecules participate in stem cell proliferation, differentiation, and development of cellular structures, and play fundamental roles in changing stem cells into somatic cells that have specialized physiological completion of their physiological functions, somatic cells will go to die and then be degraded into small molecules, such as amino acids, monosaccharides, and lipids for energy the same time, stem cells begin to proliferate and differentiate into new somatic cells so as to replace the dead on these two pathways for the metabolism of food, all metabolisms in our body form a circle (Fig.2).Fig.2 Two core processes in multicellular lifeNow, we can abstract all behaviors of our body into two fundamental processes and draw a conclusion that the essence of multicellular life may be considered as a highly regulated energy metabolism based on SCPD(Fig.2).Although energy metabolism can afford all energy for all of our behaviors and organ functions in our body, it should not be denied that the whole process of energy metabolism can be imitated in , the SCPD is the fundamental characteristic in the multicellular creatures which differentiate them from non-living , we can launch a bold declaration that all of our behaviors including all physiologies and pathologies are based on the interrelationships between energy metabolism and , the interrelationships between energy metabolism and SCPD are so complicated and similar to that of yin and yang in traditional Chinese medicine (TCM).In other words, energy metabolism and SCPD are both relatively independent and inseparable processes in multicellular energy metabolism, the basic materials and energy for SCPD are not available; without SCPD, energy metabolism cannot proceed in our , both processes appear to be necessary to sustain multicellular life.As for SCPD, it is a vital physiological process for resisting pathogen invasion and self-repairing from infection while the abnormality of SCPD will afford the opportunities for the occurrences of is needed to maintain the integrity of mucosal barriers, which protect against pathogen invasionThe general idea is that the immune system is the main defense against the pathogen invasion while we should note that the immune system must rely on the normality of SCPD.The immune system is divided into the innate immune system, which provides non-specific immunity and is presented in most organisms, and the adaptive immune system, which provides specific immune responses and is only presented in higher pathogens initially encounter the innate immune system, which primarily consists of mucosal barriers and particular, the mucosal layer is the first barrier against the pathogen invasion for damaging or destroying the mucosal barrier is the initial step of pathogen invasion, which will lead to the exposure of submucosal tissue and elicitation of an inflammatory inflammatory reactions will lead to further destruction of the mucosal barrier and exacerbation of the the human body, all mucosal barriers,including skin mucosa, respiratory mucosa, intestinal mucosa, and urethral mucosa are made of epithelial cells also have the capacity of example, skin epithelial cells are renewed every 2 weeks, and intestinal epithelial cells are renewed every 3-5 epithelial cells die, the mucosal stem cells will produce new somatic cells by proliferation and new cells will take the place of dead cells, thereby maintaining mucosal barrier the early stage of infection, epithelial cells die because of pathogen this time, multipotent or/and unipotent stem cells will undergo accelerated proliferation and differentiation, resulting in the production of somatic cells that replace the dead cells, the maintenance of mucosal barrier integrity, and the resistance to pathogen the production of new somatic cells cannot keep pace with the death of older cells, the mucosal barrier will be damaged or destroyed, and pathogens continue to destroy cells and tissues as they triggers a submucosal inflammatory response and the progression of infection in the human cells produce immune cells against specific pathogens by proliferation and differentiationWhite blood cells are the main cells for wiping off the invading pathogens in our , blood cells, as the specialized cells, are the products of are two main types of human white blood cells that resist pathogen invasion: granulocytes (neutrophils,eosinophils, and basophils), which have nonspecific immune functions, and lymphocytes (T cells, B cells,and natural killer cells), which have specific immune cells can proliferate, and are classified as unipotent stem , the initiation of pathogen invasion activates specific lymphocytes to begin proliferation and differentiation, and these newly produced lymphocytes play roles in elimination of the , lymphocyte differentiation is an important physiological process that protects against pathogen , which can phagocytize pathogens and necrotic tissues, are a specialized type of somatic cells that cannot undergo proliferation and , granulocytes are derived from bone marrow stem cells, which can continue to produce granulocytes by particular, bone marrow stem cells differentiate into different intermediate cell types (myeloblasts and progranulocytes), which then differentiate into course, bone marrow stem cells can also differentiate into lymphocytes, and these cells can move to spleen, thymus, lymph nodes, and other regions where they undergo further the mucosal barriers are destroyed by pathogen invasion, there is a localized inflammatory the early stage of inflammation, granulocytes infiltrate the damaged tissue and phagocytize pathogens, and this helps to prevent pathogen , lymphocyte infiltration occurs, and this adaptive immune response kills specific of the immune cells,being recruited to this local inflammatory tissue, will the death of these immune cells, bone marrow stem cells produce new granulocytes and lymphocytes to compensate for the dead cells, and the continued production of these cells reduces the inflammatory response and gradually eliminates the invading , chemotherapy, hematological malignancies, and certain other diseases inhibit the processes of bone marrow SCPD.In such cases, serum levels of granulocytes and/or lymphocytes may decline,or these cells may develop functional abnormalities,making the body more vulnerable to this condition persists, bacteria will multiply and spread,possibly leading to opportunistic infections, bacteremia,sepsis, septic shock, disseminated intravascular coagulation, and even death.In such cases, improvement of granulocyte function appears to be the best way to prevent and resist utilization of filgrastim, an analogue of human granulocyte colonystimulating factor (G-CSF) has confirmed that treatment with G-CSF can reduce the infectious complications of cytotoxic trial also shows that treatment with granulocyte-macrophage colonystimulating factor in patients with postoperative immune suppression is safe and effective in restoring monocytic immune competence[34].SCPD helps to repair tissues in the later stage of infectionDuring the initial physiological processes in which immune cells eliminate pathogens, the local inflammatory reaction leads to tissue destruction (Fig.3).At the later stage, it is necessary to repair the local mucosal barrier and tissue, which should be regarded as opinion is that autopoiesis must be based on SCPD for stem cells continue to proliferate and differentiate at the later stage of infection, which will result in the production of a variety of specialized cells, for repairing damaged tissue and restoring the body to full health[35].In the case that the stem cells cannot produce sufficient numbers of specialized somatic cells, there will be incomplete repair of the destroyed tissue or the process of local tissue repair will be will lead to persistence of local inflammation, failure to recover from infectious disease, and the development of conditions such as inflammatory pseudotumor, polyp, ulcer, cirrhosis, or pulmonary studies are investigating the use of hepatocyte growth factor, a cytokine that regulates diverse cellular functions, as a drug to promote tissue repair by stimulation of SCPD in inflammatory liver diseases[36].SCPD is an intrinsic factor that fights against infectionSCPD is a core physiological process of autopoiesis that plays an important role in the fi ght against invading pathogens throughout the whole process of play direct roles in the early and middle stages of infections, but anti-microbial treatment,although simple, is often insufficient to assure full , which occurs throughout the entire course of an infection, is an intrinsic factor that fi ghts against pathogen invasion in our , we propose that the ideal treatments against the infectious diseases include killing the invading pathogens and providing an advantage internal environment for SCPD.At different stages of infection, different types of stem cells undergo the process of proliferation and differentiation to produce different specialized somatic cells that fight against should take a holistic and comprehensive approach in their treatment of the entire course of infection, and should use the best available medicines to treat the later stage of infection by promoting ,more researches are needed to identify the molecular mechanisms of SCPD so that new medicines and treatments can be , infection may be a war between pathogens and SCPD in our body.In this war, the normal SCPD is disturbed by the invading of killing pathogens and affording beneficial condition for SCPD are the ideal therapies for the patient to get recovery from infectious , clinicians pay more attention to finding out the pathogens and killing them so that recent clinic applications of stem cell only focus on the transplantation of stem cells.In fact, there are few ideal parameters for clinicians to evaluate the SCPD while the occurrence of infections only implies that SCPD in our body has already been out of division and differentiation of stem cells are complex processes that are affected by many endogenous and exogenous our opinions,infectious diseases can be prevented by stimulation of stem cell division with the use of medicine such as fi lgrastim, a derivative of human granulocyte stimulating factor[34].There appears to be potential for the use of other immunomodulators, such as thymopentin, to promote lymphocyte proliferation and prevent , more alternative medicines should be developed to regulate the SCPD or to keep SCPD in order so as to cure or/and prevent the other hand, we also pointed out that the interrelationships between energy metabolism and SCPD are similar to that of yin and yang in TCM, which may bring some new understandings of the yin and yang in understandings will enlighten us to integrate the TCM and modern medicine and help us to develop new medicines to treat and prevent infectious diseases by regulating the SCPD on the principle of Stem cells against infectionDeclaration of conflicting interestsThe authors declare that there is no conflict of interests regarding the publication of this ’contributionsXiao DS conceived of the manuscript, collected data,wrote the initial draft and revised the H participated in the manuscript design and helped to draft the HY helped to collect data and participated in the interpretation of the data.Li SJ contributed to the study coordination, technical issues and revision of the authors read and approved the fi nal all confirm that all studies about this manuscript have been carried out within an appropriate ethical framework.[References][1] Moxnes JF, Moen AE, Leegaard the time trend of Methicillin-resistant Staphylococcus aureus(MRSA) in Norway by use of non-stationary γ-Poisson distributions[J].BMJ Open, 2015, 5(10):e007163.[2] Pottinger Staphylococcus aureus infections[J].Med Clin North Am, 2013, 97(4):601-619.[3] Chang CY, Lin HJ, Li BR, et al.A novel metallo-βlactamase involved in the ampicillin resistance of Streptococcus pneumoniae ATCC 49 136 strain[J].PLoS One, 2016, 11(5):e0.[4] Huang S, Liu 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controlled trial[J].PLoS One,2015, 10(12):e0.[35] Nicolay NH, Lopez Perez R, Debus J, et stem cells—A new hope for radiotherapy-induced tissue damage?[J].Cancer Lett, 2015, 366(2):133-140.[36] Huang HP, Chang MH, Chen YT, et elevation of hepatocyte growth factor activator inhibitors in cholangiopathies affects liver fi brosis and differentiation[J].Hepatology, 2012, 55(1):161-172.

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