Research Area

Cell Differentiation


Introduction of cell differentiation

Cell differentiation refers to the process in which cells of the same source gradually produce cell groups with different morphological structures and functional characteristics. As a result, cells are spatially different, and the same cells differ in time from their previous state. The essence of cell differentiation is the selective expression of the genome in time and space. The expression of different genes is turned on or off, and finally, the iconic protein is produced. In general, the process of cell differentiation is irreversible. However, under certain conditions, the differentiated cells are also unstable, and their gene expression patterns can also undergo reversible changes and return to their undifferentiated state. This process is called dedifferentiation. Features of cell differentiation include: The potential of differentiation gradually appears with the development of the individual. During embryonic development, the cells gradually change from "all-around" to "multi-energy", and finally to the "single-energy", which is the general rule of cell differentiation. In the process of individual development, multicellular biological cells have both temporal differentiation and spatial differentiation; cell differentiation is compatible with the state and speed of cell division, and differentiation must be based on division, that is, differentiation is inevitable with division, but the dividing cells do not necessarily need differentiate. The higher the degree of differentiation, the worse the ability to divide; the cell differentiation is highly stable. Under normal physiological conditions, cells that have differentiated into a specific, stable type are generally impossible to reverse to undifferentiated state or become other types. Cell differentiation is plastic, and the differentiated cells re-enter the undifferentiated state or transdifferentiate into another type of cell under special conditions.

Cell differentiation and related regulation factors

Embryonic stem cells (ES cells) have the potential to develop into different types of cells. Under suitable conditionsin vitro, they can proliferate in an undifferentiated state, providing a source of cells for the research and application of ES cells. The mouse embryonic stem cells treated with retinoic acid will differentiate into neural progenitor cells and then treat with Shh specific small molecule antagonist Hh-Ag 1. 3 to differentiate into motor neurons. Hori et alconfirmed that the PI3-K inhibitor LY294002 can promote the differentiation of embryonic stem cells cultured into insulin-producing β cells, and further clarify that the differentiated β cells can improve insulin levels in vivo, prevent weight loss, and control blood glucose concentration. Takahashiet alfound that ascorbic acid can effectively enhance the differentiation of embryonic stem cells into cardiomyocytes. Wuet al. recently synthesized and screened many small molecule chemical libraries that can effectively induce mouse embryonic stem cells to differentiate into cardiomyocytes by combinatorial chemical combination and obtained a series of bis-aminopyrimidine compounds with such orientation induction. Hironori et al. also used microarray technology to detect differentiation of embryonic stem cells. Of course, due to the existence of immunocompatibility issues, the safety of embryonic stem cell transplantation needs to be a comprehensive, objective and in-depth evaluation. Bone marrow stromal cells (MSCs) are derived from mesoderm and can differentiate into mesoderm cells such as osteoblasts, chondrocytes, myoblasts, tendon cells, adipocytes, and stromal cells under certain induction conditions; it can differentiate into neuroblast cells of the ectoderm and hepatic oval cells of the endoderm. Due to its wide source of materials and the low degree of immune rejection during transplantation, it is a target cell for cell replacement therapy with the good clinical application. Many research groups conducted in vitrodifferentiation experiments of MSCs under in vitroculture conditions. Woodbury et al. successfully induced the conversion of MSCs into neurons with β-mercaptoethanol (BME), dimethyl sulfoxide (DMSO) and butylated hydroxyanisole (BHA) and expressed neuron-specific markers. Denget al.combined the use of isobutylmethylxanthine (IBMX) and dibutyl cyclic adenosine monophosphate (dbcAMP) to increase intracellular cAMP levels and converted MSCs into neuron-like cells. MSCs can differentiate into osteoblasts under the induction of dexamethasone, sodium 8-glycerophosphate and vitamin C. Dexamethasone can regulate gene expression in differentiated cells and promote the transformation into osteoblasts by enhancing the affinity of its receptors to genomic target sequences. It is an essential component of osteogenic differentiation of MSCs in vitro, and vitamin C is also an important inducer. Amphotericin B can differentiate MSCs into myocytes, and some scholars have used the MSCs of rats to conduct muscle differentiation. It is found that both 5-azacytidine and 5-az-2-deoxycytidine can promote MSCs to muscle differentiation. Currently, inducers that induce differentiation of MSCs into neuron-like cells are mainly antioxidants and calcium channel blockers. Antioxidants may bind to certain specific receptors on the surface of MSCs, thereby initiating one or more signaling pathways that ultimately differentiate into neurons. For example, MSCs treated with the small molecule compound D609 showed significant morphological changes, demonstrating that antioxidant D609 can induce MSCs to differentiate into neuron-like cells. Most of the experiments in recent years have used some antioxidants, and the traditional Chinese medicine Salvia miltiorrhiza contains various antioxidant components such as tanshinone and total salvianolic acid. Qingtao et al. induced the monkey MSCs with cryptotanshinone. The induced cells were analyzed by immunocytochemistry, and NSE and NF were positive, and GFAP expression was negative. Because Salvia miltiorrhiza is a commonly used traditional Chinese medicine for activating blood circulation and removing stasis, it has no toxic side effects and is safe, so it has high practical value. In addition, Chinese herbal medicines such as Chinese angelica, ginseng, gastrodia elata, and astragalus can also induce MSCs to differentiate into nerve cells because these Chinese medicine ingredients have similar antioxidant effects as β-mercaptoethanol. Calcium channel blockers can alleviate damage caused by calcium influx during spinal cord and visual cord injury. It has protective effects on neurons, such as total saponins of Panax notoginseng, ligustrazine, and berberine. Berberine is a calcium channel blocker that protects neuronal apoptosis. Bone marrow mesenchymal stem cells have multi-directional differentiation potential in addition to their hematopoietic microenvironment. Under certain conditions, they can differentiate into osteoblasts and fat cells, muscle cells and neuron-like cells. Neural stem cells (NSCs) are cells that can differentiate into neurons, astrocytes, and oligodendrocytes, capable of self-renewal and capable of producing large amounts of neural tissue cells. It has a variety of differentiation potential and self-renewal capabilities. The subependymal layer, hippocampus, and dentate gyrus near the lateral ventricle are currently recognized as the most concentrated sites of neural stem cells in the adult mammalian nervous system. The development and differentiation of neural stem cells depend on the specific genes at specific sites and timetables and is regulated by both neurotrophic factors and the internal environment. In theory, any type of central nervous system disease can be attributed to a disorder of neural stem cell function. Due to the presence of the blood-brain barrier, the brain, and spinal cord do not produce immune rejection after stem cells are transplanted into the central nervous system. For example, transplanting brain cells containing dopamine-producing cells into the brain of patients with Parkinson's syndrome can cure parts of patient symptoms. Ginkgolide B can promote the differentiation of cultured neural stem cells into neurons. Ding Ying et al.induced the differentiation of cultured neural stem cells with ginkgolide B. The results showed that ginkgolides B promoted the differentiation of neural stem cells into neuron-like cells in a certain concentration. Green standard uses SNP as a donor of exogenous NO to study the effect of NO on the differentiation of neural stem cells. It is found that NO can promote the differentiation of neural stem cells and promote the development of axons after cell differentiation. In addition, sodium salicylate has a significant regulatory effect on GABA and Glu protein expression in neurons of the inferior colliculus. Yin Shihua et al found that sodium salicylate promotes the differentiation of neural stem cells into Gluergic neurons and inhibits the differentiation of neural stem cells into GABA ergic neurons. The regulation of neural stem cell differentiation and differentiation is a major topic in neural stem cell research. Neural stem cell culture techniques can be used to observe the neuronal activity of certain natural compounds and synthetic compounds and provide a theoretical basis for the development of small molecule therapeutic drugs.

Function of cell differentiation

The rapid development of stem cell biology has provided us with a strong support for further understanding of the precise molecular regulation mechanisms in the development of organisms, as well as new treatments for cancer, cardiovascular and cerebrovascular diseases, neurodegenerative diseases, diabetes, and other diseases. It brought hopes to neurological diseases. Therefore, before the therapeutic potential of stem cells is widely applied to the clinic, it is necessary to have a deeper understanding of the characteristics and regulatory mechanisms of stem cell proliferation and differentiation that determine the stem cell fate, to survive and proliferate through the endogenous cells. Differentiation and migration activate the organism's own regeneration mechanism to achieve the purpose of curing the disease. Although small molecules have been screened for new drug development and cell biology research on a cell basis for decades, the importance of these small molecules in stem cell research has just been recognized. The means of chemical genetics are controllable and reversible – small molecule compounds can be added or removed at any time to initiate or interrupt specific reactions. Most small molecule compounds act very fast on proteins, allowing for real-time detection. Furthermore, by controlling the concentration of the compound, the kinetics of the target molecule to which it acts can be analyzed. And an identical small molecule compound can be widely used to affect a certain process or function of different organisms. However, no matter how to explain the special mechanism of action of these small molecules, small molecules that can effectively induce stem cell differentiation in vitro have the same effectin vivo, and the function of cells treated by these small molecules will not change compared with normal cells. Undoubtedly, the identification and screening of more and more small molecules that determine the fate of stem cells will significantly promote the development of stem cell biology and the development of regenerative drugs.

Reference

  1. Asaoka Y, Hata S, Namae M, et al. The Hippo Pathway Controls a Switch between Retinal Progenitor Cell Proliferation and Photoreceptor Cell Differentiation in Zebrafish. Plos One. 2014, 9(5)e97365.
  2. Cerdáesteban N, Spagnoli F M. Glimpse into Hox and tale regulation of cell differentiation and reprogramming. Developmental Dynamics. 2014, 243(1):76-87.
  3. Regalo G, Leutz A. Hacking cell differentiation: transcriptional rerouting in reprogramming, lineage infidelity and metaplasia. Embo Molecular Medicine. 2013, 5(8):1154-1164.

Evans C M, Jenner R G. Transcription factor interplay in T helper cell differentiation. Briefings in Functional Genomics. 2013, 12(6):499-511.

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