Research Area

Tissue Regeneration


Tissue regeneration overview

Tissue regeneration is a part of the organism's tissue that is traumatized by external forces and partially lost. Based on the remaining part, it grows the same structure and function as the lost part. This repair process is called tissue regeneration. Tissue regeneration includes regeneration of epithelial tissue, regeneration of fibrous tissue, regeneration of cartilage tissue and bone tissue, regeneration of blood vessels, regeneration of muscle tissue, and regeneration of nerve tissue. As a hot spot in clinical research, tissue regeneration is expected to be used in the treatment of many damaged diseases in tissues, but the specific mechanism remains to be further studied.

Tissue regeneration research status

It is generally believed that the reason why mammals cannot undergo progressive regeneration is that the differentiated tissues cannot be dedifferentiated and re-entered into the cell cycle for proliferation. Muscle microtubules are multinucleated cells that are fused by myoblasts. The process of dedifferentiation can be visually observed by observing changes in the number of nuclei. Therefore, this model provides convenience for studying factors involved in dedifferentiation. Previous studies have shown that thrombin does not reinvigorate into the cell cycle of muscle microtubules formed by the differentiation of mouse C2C12 cells as it acts on diaphragmatic microtubule cells, so it was thought that mammals had at least a difference in regenerative capacity at the cellular level. The work of Keating Labs shows that the difference between mammalian and amphibious regeneration may not be as great as previously thought. When an extract of sputum regenerated buds was added to the muscle microtubules formed by in vitro differentiation of A1 cells and mouse C2C12 cells, both dedifferentiation occurred. This means that mammals themselves do not lack the endogenous signaling pathways required for dedifferentiation, but because of the lack of exogenous signals that trigger dedifferentiation, the mammals are unable to regenerate. The msx1 gene encodes a nuclear transcriptional repressor containing a homeobox, which plays an important role in the dedifferentiation of sputum cells. When msx1 is expressed in muscle microtubules formed by in vitrodifferentiated mouse C2C12 cells, the cells undergo dedifferentiation. These experiments have shown that mammals maintain the ability to dedifferentiate and regenerate at least at the cellular level, but our understanding of the molecular mechanism of the process of dedifferentiation is still very preliminary, and more basic research must be done to provide a theoretical basis for clinical research. Regeneration of central nervous system axons damage to the central nervous system, it is usually accompanied by severe damage to the axons and death of the neurons. Therefore, there are two ideas for treating nervous system damage diseases: one is to implant exogenous stem cells or partially differentiated neurons at the injury site to differentiate the damaged neurons; the second is to activate the nervous system to the maximum extent. The ability to regenerate itself, thereby repairing the damaged nervous system. Of the two approaches, the former has received widespread attention, and a recent series of studies on axonal regeneration in the central nervous system suggests that the latter may be a more effective approach. In fact, mammalian central nervous system axons are regenerative, but their regeneration is inhibited by certain factors in the surrounding environment, especially myelin. Myelin is a complex composed of oligodendrocytes and contains a variety of lipids and proteins. When damaged nerve fibers are exposed to it, regeneration is inhibited. This indicates that the myelin must contain a component that inhibits axonal regeneration. Three of these molecules have been shown to inhibit axonal regeneration, namely Nogo-A molecule, myelin-associated glycoprotein (MAG) and oligodendrocyte myelin. The Nogo-A molecule contains two domains that inhibit axon regeneration. One of the inhibitory domains is a 66-amino acid sequence located on the outer surface of the oligodendrocyte, known as Nogo66. Nogo-66, MAG, and OMgp share a common receptor, the Nogo receptor (NgR), which in turn is anchored to the neuronal cell membrane by glycosylphosphatidylinositol. Nogo-66, MAG, and OMgp can bind to NgR, and then NgR transmits a signal to the membrane through the transmembrane P75 protein, through a series of intramembrane proteins such as Rho guanylate triphosphatase, and finally inhibits the regeneration of axons. Since the three inhibitory molecules have a common receptor, it is envisaged whether the damaged axons can be regenerated by inactivating the NgR. Experiments have shown that removal of GPI-conjugated proteins, transfection of cells with loss of function with NgR, or addition of antibodies to NgR eliminates the inhibition of axonal regeneration by the three molecules. Although these results must be done in the treatment, it does provide a new way of thinking about the treatment of nerve damage. An important model of mammalian regeneration research - MRL strain mice. It was previously thought that only lower vertebrate animals had the ability to regenerate, while mammals could not regenerate. When a mammal is damaged, fibroblasts migrate to the damaged site to form granule tissue and finally form an unstructured scar mainly composed of collagen. However, in 1998, Heber-Katz et al. found that MRL strain mice also have the regenerative ability and conducted a series of in-depth studies using this model. MRL strains of mousefas gene mutants can rapidly proliferate to cause autoimmune diseases, initially used as an experimental model of systemic lupus erythematosus. However, the pores used to label the MRL strain on the ears of mice can be closed in a short period of time, unlike the mice of other strains, which are crusted and cause permanent damage. In less than 4 weeks, a 2 mm diameter hole in the MRL strain mouse ear can be closed, and the regenerated part has normal dermis, tissue-ordered ECM, vasculature, and cartilage. After the injury, the epithelial cells of this strain will rapidly migrate to the wound, and the wound will not be crusted but form a ring-like swelling like the amphibian regenerative bud. The cells such as dermis and cartilage will dedifferentiate. Moreover, the ability of wound healing is quantitatively inherited. Through genetic phenotype and genome-wide genetic screening analysis, it is proved that the regeneration of this strain mouse is not related to the mutation of fas gene, because both wild-type andfas mutant individuals have the same ability to regenerate. Seven genes associated with regeneration and quantitative traits have been mapped to different chromosomes. These regeneration-related candidate genes include genes associated with amphibious regeneration, such as retinoic acid receptors γ and msx2. Through the EST technology, some genes expressed in the inflammatory phase were also identified in the MRL strain, and many genes with unknown functions were also involved in this complex process. For example, the class of delta protein Pref-1, which maintains the undifferentiated state of cells, has been identified to increase expression in damaged ears. MRL strains not only regenerate the ear but also partially regenerate the heart. The MRL strain mice were cut open, and the right ventricle was partially necrotic with a cryoprobe. After suturing, the heart was fully regenerated and restored after 2 months. During this process, the mitotic index of cardiomyocytes was significantly higher than that of the control group, and the expression of collagen increased on the 5th day after the injury but decreased significantly after the 15th day, which was related to the regeneration process in the amphibians. The change in the amount of collagen expression is not a decrease in the transcription of its mRNA, but there may be some protease that destroys the expressed collagen, so it cannot form sputum. Recently, the matrix metalloproteinase (MMP) identified in ear regeneration tissue may be this protease.

Tissue regeneration influence factors

In recent years, regenerative medicine research has become one of the hotspots in the field of medical research. The application of tissue engineering technology to construct engineering lungs to replace transplanted lung tissue has become a new choice and research direction. Although the complex three-dimensional structure of the lungs and the characteristics of various cell components make it relatively backward in the research of regenerative medicine, its development prospects are still expected. Now summarize some of the factors that can promote tissue regeneration: Hepatic cytokines are a pluripotent growth factor. Studies have shown that HGF exerts its mitogenic, pre-forming and lung protection effects during the development of lung and after lung injury by phosphorylation of the tyrosine kinase of its receptor c-Met. Both in vivo and in vitrostudies have shown that HGF is an effective mitogen in alveolar type II epithelial cells. The role of HGF in lung regeneration has also been extensively studied. Peritoneal application of HGF can significantly increase the proportion of Sca-1+ / Folk-1+ cells in peripheral blood mononuclear cells of mice and promote the proliferation of endothelial cells in the alveolar wall and the presence of endothelial cells in the alveolar wall itself, thereby reversing elastase change caused by emphysema in mice. Current research has confirmed that HGF has a role in promoting lung regeneration, but clinical studies are still needed for further validation. Keratinocyte growth factor (KGF), also known as fibroblast growth factor 7 (FGF7), has a growth factor during wound healing that promotes keratinocyte growth, wound repair and healing. Alveolar type II epithelial cells (AEII) express the KGF receptor. Studies have found that KGF can promote the proliferation, migration, and survival of AEII. Whether KGF has the repairing effect of alveolar damage is controversial. KGF can prevent emphysema-induced emphysema in mice, but the application of KGF after 3 weeks of elastase application does not reverse alveolar destruction. This suggests that KGF has a more prominent role in anti-inflammatory. Granulocyte colony-stimulating factor (G-CSF), also known as colony-stimulating factor 3 (CSF3), is a glycoprotein that can be produced by a variety of tissues, stimulates the bone marrow to produce granulocytes and stem cells, and is released into the blood. G-CSF also has a role in promoting tissue regeneration. Studies have confirmed that after myocardial necrosis in mice, GCSF can promote the release of bone marrow stem cells into the blood, and finally differentiate into cardiomyocytes, which can promote tissue regeneration. Adrenomedullin (ADM) is a pheochromocytoma originally isolated from adrenal medullary tumors and is a multifunctional regulatory peptide that induces the production of cAMP, dilates the bronchi, regulates cell growth, inhibits apoptosis and angiogenesis. Airway epithelial basal cells and alveolar II epithelial cells are abundantly distributed with ADM receptors. It is believed that ADM may be involved in lung tissue regeneration. Murakami et al. continued to use ADM in elastase-induced mouse emphysema, which can significantly increase peripheral blood Sca-1+ cells and simultaneously regenerate alveolar and blood vessels. This suggests that ADM can mobilize bone marrow-derived cells into the bloodstream while providing direct protection to alveolar epithelial cells and endothelial cells.

Reference

  1. Zhan W, Chang Q, Xiao X, et al. Self-synthesized extracellular matrix contributes to mature adipose tissue regeneration in a tissue engineering chamber.Wound Repair & Regeneration. 2015, 23(3):443-452.
  2. Seifert A W, Kiama S G, Seifert M G, et al. Skin shedding and tissue regeneration in African spiny mice (Acomys). Nature. 2012, 489(7417):561.
  3. Birbrair A, Zhang T, Wang Z M,et al. Pericytes at the intersection between tissue regeneration and pathology. Clinical Science. 2015, 128(2):81.

Mu X, Bellayr I, Pan H,et al. Regeneration of soft tissues is promoted by MMP1 treatment after digit amputation in mice. Plos One. 2013, 8(3): e59105

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