Immune system contribution to regeneration

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Immune system contribution to regeneration of tissues generally involves specific cellular components, transcription of a wide variety of genes, morphogenesis, epithelia renewal and proliferation of damaged cell types (progenitor or tissue-resident stem cells). However, current knowledge reveals more and more studies about immune system influence that cannot be omitted. As the immune system exhibits inhibitory or inflammatory functions during regeneration, the therapies are focused on either stopping these processes or control the immune cells setting in a regenerative way, suggesting that interplay between damaged tissue and immune system response must be well-balanced. Recent studies provide evidence that immune components are required not only after body injury but also in homeostasis or senescent cells replacement.

Contents

Macrophages

Both phenotypes of macrophages (M1 and M2) are one of the most important regenerative components of the immune system as their dysfunction inhibits tissue repair and blastema formation. M1 macrophages are known as pro-inflammatory, (secreting cytokines IL-1, IL-6, TNF- α, and IFN-γ) playing a crucial role in pathogen phagocytosis and cell debris clearance and molecules that promote inflammation in comparison with M2 macrophages (anti-inflammatory macrophages secreting IL-10 and VEGF) [1] that inhibit inflammation and initiate regenerative processes in the site of injury. Both must be polarized correctly and at the right time during the healing processes. [2] [3]

T-regulatory cells

Skeletal muscle regeneration in the site of injury accumulates T-reg cells as a response to IL-33. T-reg cells directly induce M1/M2 phenotype of macrophages so they change the outcome and manage the processes in time. Another important function od T-regs is their activation of muscle cells precursors and proliferation of these cells by growth factors for example amphiregulin. [4]

Scavenger cells

Immune components are necessary in cellular debris clearance in order to avoid toxic products of dead or necrotic cells and to create space for the renewal of tissue and its incorporation into the organ. The main cells that are involved in this particular process are M1 macrophages also called scavengers. Phagocytosis of dead tissue can consequently activate the signaling cascade necessary for regeneration. For instance, the macrophages phagocytosis in liver of dead or necrotic hepatocytes induces Wnt expression, which can influence the proliferation and differentiation of hepatic progenitor cells into liver cells. [5]

Stem and progenitor cells regulation

Immune cells under the control of inflammatory cytokines and setting secrete molecules that can promote proliferation and differentiation of progenitors and stem cells and in certain organism also dedifferentiation of the tissue. ¨

For example, zebrafish regeneration of the nerve tissue is followed by brain injury and inflammation that activate microglia and leukocytes. The secretion of Leukotriene C4 consequently activates the radial glial cells (neural progenitors) and induce regeneration. [6]

Also, neutrophils and macrophages in rats secrete growth factor oncomodulin that support axonal regeneration in the CNS. Microglia and macrophages together help in the oligodendrocyte remyelination. [7]

Intestinal injury of the epithelia activates macrophages that secrete a wide range of survival and growth progenitor factors which is very similar to muscle regeneration. M1 macrophages induce proliferative environment by secreting cytokines IL6, TNF, IL1, and G-CSF. [8]

Dedifferentiation

Dedifferentiation is a pathway in which already differentiated tissue come back reversely in the process of differentiation. Cells loose differentiated setting and are becoming progenitor or stem cells again. Afterwards they can differentiate again into other cell types (usually like the tissue of origin). Thus, dedifferentiation displays the ability of regeneration in the absence or scarcity of stem or progenitor cells.

Recent studies discovered macrophages as an initial factor that contribute to the dedifferentiation of the cells in the site of injury and promote the formation of the progenitor cell pool during limb regeneration in the salamander. Molecules such as Oncostatin M are considered as a mediator of cardiomyocyte dedifferentiation and morphogenesis factor during myocardial infarction and chronic cardiomyopathy. [9]

Angiogenesis

Angiogenesis and branching of the veins are dependent on eosinophils, mast cells and myeloid cells during development. [10] During the regeneration, blood flow is necessary to support tissue repair and remodeling. Key ligands expressed by macrophages Wnt5a and Wnt11 enhance the expression of the VEGF inhibitory receptor Flt1 so that blocking this pathway supports vascularization. [11]

Other study focuses on heart injury. They found that during the late phase of scar formation M2 macrophages are needed for vascularization together with fibrosis to form a scar. Monocyte depletion impaired heart regeneration due to insufficient neoangiogenesis in mice. [12] Even though there are different types of macrophages involved in wide range of processes that are still uncertain, the study suggests that macrophages promoting human heart regeneration might promote angiogenesis without fibroblasts activation. [13]

Related Research Articles

A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes.

<span class="mw-page-title-main">Macrophage</span> Type of white blood cell

Macrophages are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris, and foreign substances, which do not have proteins that are specific to healthy body cells on their surface. This process is called phagocytosis, which acts to defend the host against infection and injury.

<span class="mw-page-title-main">Healing</span> Process of the restoration of health

With physical trauma or disease suffered by an organism, healing involves the repairing of damaged tissue(s), organs and the biological system as a whole and resumption of (normal) functioning. Medicine includes the process by which the cells in the body regenerate and repair to reduce the size of a damaged or necrotic area and replace it with new living tissue. The replacement can happen in two ways: by regeneration in which the necrotic cells are replaced by new cells that form "like" tissue as was originally there; or by repair in which injured tissue is replaced with scar tissue. Most organs will heal using a mixture of both mechanisms.

<span class="mw-page-title-main">Wound healing</span> Series of events that restore integrity to damaged tissue after an injury

Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue.

<span class="mw-page-title-main">Striated muscle tissue</span> Muscle tissue with repeating functional units called sarcomeres

Striated muscle tissue is a muscle tissue that features repeating functional units called sarcomeres. The presence of sarcomeres manifests as a series of bands visible along the muscle fibers, which is responsible for the striated appearance observed in microscopic images of this tissue. There are two types of striated muscle:

<span class="mw-page-title-main">Kupffer cell</span> Macrophages located in the liver

Kupffer cells, also known as stellate macrophages and Kupffer–Browicz cells, are specialized cells localized in the liver within the lumen of the liver sinusoids and are adhesive to their endothelial cells which make up the blood vessel walls. Kupffer cells comprise the largest population of tissue-resident macrophages in the body. Gut bacteria, bacterial endotoxins, and microbial debris transported to the liver from the gastrointestinal tract via the portal vein will first come in contact with Kupffer cells, the first immune cells in the liver. It is because of this that any change to Kupffer cell functions can be connected to various liver diseases such as alcoholic liver disease, viral hepatitis, intrahepatic cholestasis, steatohepatitis, activation or rejection of the liver during liver transplantation and liver fibrosis. They form part of the mononuclear phagocyte system.

<span class="mw-page-title-main">Microglia</span> Glial cell located throughout the brain and spinal cord

Microglia are a type of neuroglia located throughout the brain and spinal cord. Microglia account for about 10-15% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune defense in the central nervous system (CNS). Microglia originate in the yolk sac under a tightly regulated molecular process. These cells are distributed in large non-overlapping regions throughout the CNS. Microglia are key cells in overall brain maintenance—they are constantly scavenging the CNS for plaques, damaged or unnecessary neurons and synapses, and infectious agents. Since these processes must be efficient to prevent potentially fatal damage, microglia are extremely sensitive to even small pathological changes in the CNS. This sensitivity is achieved in part by the presence of unique potassium channels that respond to even small changes in extracellular potassium. Recent evidence shows that microglia are also key players in the sustainment of normal brain functions under healthy conditions. Microglia also constantly monitor neuronal functions through direct somatic contacts and exert neuroprotective effects when needed.

Stromal cells, or mesenchymal stromal cells, are differentiating cells found in abundance within bone marrow but can also be seen all around the body. Stromal cells can become connective tissue cells of any organ, for example in the uterine mucosa (endometrium), prostate, bone marrow, lymph node and the ovary. They are cells that support the function of the parenchymal cells of that organ. The most common stromal cells include fibroblasts and pericytes. The term stromal comes from Latin stromat-, "bed covering", and Ancient Greek στρῶμα, strôma, "bed".

<span class="mw-page-title-main">Hepatocyte growth factor</span> Mammalian protein found in Homo sapiens

Hepatocyte growth factor (HGF) or scatter factor (SF) is a paracrine cellular growth, motility and morphogenic factor. It is secreted by mesenchymal cells and targets and acts primarily upon epithelial cells and endothelial cells, but also acts on haemopoietic progenitor cells and T cells. It has been shown to have a major role in embryonic organ development, specifically in myogenesis, in adult organ regeneration, and in wound healing.

<span class="mw-page-title-main">Colony stimulating factor 1 receptor</span> Protein found in humans

Colony stimulating factor 1 receptor (CSF1R), also known as macrophage colony-stimulating factor receptor (M-CSFR), and CD115, is a cell-surface protein encoded by the human CSF1R gene. CSF1R is a receptor that can be activated by two ligands: colony stimulating factor 1 (CSF-1) and interleukin-34 (IL-34). CSF1R is highly expressed in myeloid cells, and CSF1R signaling is necessary for the survival, proliferation, and differentiation of many myeloid cell types in vivo and in vitro. CSF1R signaling is involved in many diseases and is targeted in therapies for cancer, neurodegeneration, and inflammatory bone diseases.

A macrophage-activating factor (MAF) is a lymphokine or other receptor based signal that primes macrophages towards cytotoxicity to tumors, cytokine secretion, or clearance of pathogens. Similar molecules may cause development of an inhibitory, regulatory phenotype. A MAF can also alter the ability of macrophages to present MHC I antigen, participate in Th responses, and/or affect other immune responses.

Bone-marrow-derived macrophage (BMDM) refers to macrophage cells that are generated in a research laboratory from mammalian bone marrow cells. BMDMs can differentiate into mature macrophages in the presence of growth factors and other signaling molecules. Undifferentiated bone marrow cells are cultured in the presence of macrophage colony-stimulating factor. M-CSF is a cytokine and growth factor that is responsible for the proliferation and commitment of myeloid progenitors into monocytes. Macrophages have a wide variety of functions in the body including phagocytosis of foreign invaders and other cellular debris, releasing cytokines to trigger immune responses, and antigen presentation. BMDMs provide a large homogenous population of macrophages that play an increasingly important role in making macrophage-related research possible and financially feasible.

Tumor-associated macrophages (TAMs) are a class of immune cells present in high numbers in the microenvironment of solid tumors. They are heavily involved in cancer-related inflammation. Macrophages are known to originate from bone marrow-derived blood monocytes or yolk sac progenitors, but the exact origin of TAMs in human tumors remains to be elucidated. The composition of monocyte-derived macrophages and tissue-resident macrophages in the tumor microenvironment depends on the tumor type, stage, size, and location, thus it has been proposed that TAM identity and heterogeneity is the outcome of interactions between tumor-derived, tissue-specific, and developmental signals.

Adipose tissue macrophages (ATMs) comprise resident macrophages present in adipose tissue. Besides adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells that includes pre-adipocytes, fibroblasts, vascular endothelial cells, and a large variety of immune cells. The latter ones are composed of mast cells, eosinophils, B cells, T cells and macrophages. The number of macrophages within adipose tissue differs depending on the metabolic status. As discovered by Rudolph Leibel and Anthony Ferrante et al. in 2003 at Columbia University, the percentage of macrophages within adipose tissue ranges from 10% in lean mice and humans up to 50% in obese leptin deficient mice, and up to 40% in obese humans. ATMs comprise nearly 50% of all immune cells in normal conditions, suggesting an important role in supporting normal functioning of the adipose tissue. Increased number of adipose tissue macrophages may correlate with increased production of pro-inflammatory molecules and might therefore contribute to the pathophysiological consequences of obesity, although is becoming recognized that in healthy conditions tissue-resident macrophages actively support a variety of critical physiological functions in nearly all organs and tissues, including adipose tissue.

Regulatory macrophages (Mregs) represent a subset of anti-inflammatory macrophages. In general, macrophages are a very dynamic and plastic cell type and can be divided into two main groups: classically activated macrophages (M1) and alternatively activated macrophages (M2). M2 group can further be divided into sub-groups M2a, M2b, M2c, and M2d. Typically the M2 cells have anti-inflammatory and regulatory properties and produce many different anti-inflammatory cytokines such as IL-4, IL-33, IL-10, IL-1RA, and TGF-β. M2 cells can also secrete angiogenic and chemotactic factors. These cells can be distinguished based on the different expression levels of various surface proteins and the secretion of different effector molecules.

Macrophage polarization is a process by which macrophages adopt different functional programs in response to the signals from their microenvironment. This ability is connected to their multiple roles in the organism: they are powerful effector cells of the innate immune system, but also important in removal of cellular debris, embryonic development and tissue repair.

Scar free healing is the process by which significant injuries can heal without permanent damage to the tissue the injury has affected. In most healing, scars form due to the fibrosis and wound contraction, however in scar free healing, tissue is completely regenerated. During the 1990s, published research on the subject increased; it is a relatively recent term in the literature. Scar free healing occurs in foetal life but the ability progressively diminishes into adulthood. In other animals such as amphibians, however, tissue regeneration occurs, for example as skin regeneration in the adult axolotl.

Craniofacial regeneration refers to the biological process by which the skull and face regrow to heal an injury. This page covers birth defects and injuries related to the craniofacial region, the mechanisms behind the regeneration, the medical application of these processes, and the scientific research conducted on this specific regeneration. This regeneration is not to be confused with tooth regeneration. Craniofacial regrowth is broadly related to the mechanisms of general bone healing.

Dedifferentiation is a transient process by which cells become less specialized and return to an earlier cell state within the same lineage. This suggests an increase in cell potency, meaning that, following dedifferentiation, a cell may possess the ability to re-differentiate into more cell types than it did before dedifferentiation. This is in contrast to differentiation, where differences in gene expression, morphology, or physiology arise in a cell, making its function increasingly specialized.

<span class="mw-page-title-main">Dermal macrophage</span> Skin macrophages used for wound repair and hair growth

Dermal macrophages are macrophages in the skin that facilitate skin homeostasis by mediating wound repair, hair growth, and salt balance. Their functional role in these processes is the mediator of inflammation. They can acquire an M1 or M2 phenotype to promote or suppress an inflammatory response, thereby influencing other cells' activity via the production of pro-inflammatory or anti-inflammatory cytokines. Dermal macrophages' ability to acquire pro-inflammatory properties also potentiates them in cancer defence. M1 macrophages can suppress tumour growth in the skin by their pro-inflammatory properties. However, M2 macrophages support tumour growth and invasion by the production of Th2 cytokines such as TGFβ and IL-10. Thus, the exact contribution of each phenotype to cancer defence and the skin's homeostasis is still unclear.

References

  1. ↑ Krzyszczyk, P.; Schloss, R.; Palmer, A.; Berthiaume, F. (2018). "The Role of Macrophages in Acute and Chronic Wound Healing and Interventions to Promote Pro-wound Healing Phenotypes". Frontiers in Physiology. 9: 419. doi: 10.3389/fphys.2018.00419 . PMC   5938667 . PMID   29765329.
  2. ↑ Ferrante, Christopher J.; Leibovich, Samuel Joseph (February 2012). "Regulation of Macrophage Polarization and Wound Healing". Advances in Wound Care. 1 (1): 10–16. doi:10.1089/wound.2011.0307. PMC   3623587 . PMID   24527272.
  3. ↑ Kotwal, Girish J.; Chien, Sufan (2017). "Macrophage Differentiation in Normal and Accelerated Wound Healing". Macrophages. Results and Problems in Cell Differentiation. Vol. 62. pp. 353–364. doi:10.1007/978-3-319-54090-0_14. ISBN   978-3-319-54089-4. PMC   5841920 . PMID   28455716.
  4. ↑ Schiaffino, Stefano; Pereira, Marcelo G.; Ciciliot, Stefano; Rovere-Querini, Patrizia (February 2017). "Regulatory T cells and skeletal muscle regeneration". The FEBS Journal. 284 (4): 517–524. doi: 10.1111/febs.13827 . PMID   27479876. S2CID   19730876.
  5. ↑ Boulter, Luke; Govaere, Olivier; Bird, Tom G.; Radulescu, Sorina; Ramachandran, Prakash; Pellicoro, Antonella; Ridgway, Rachel A.; Seo, Sang Soo; Spee, Bart; Van Rooijen, Nico; Sansom, Owen J.; Iredale, John P.; Lowell, Sally; Roskams, Tania; Forbes, Stuart J. (4 March 2012). "Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease". Nature Medicine. 18 (4): 572–579. doi:10.1038/nm.2667. PMC   3364717 . PMID   22388089.
  6. ↑ Kyritsis, Nikos; Kizil, Caghan; Zocher, Sara; Kroehne, Volker; Kaslin, Jan; Freudenreich, Dorian; Iltzsche, Anne; Brand, Michael (7 December 2012). "Acute inflammation initiates the regenerative response in the adult zebrafish brain". Science. 338 (6112): 1353–1356. Bibcode:2012Sci...338.1353K. doi:10.1126/science.1228773. PMID   23138980. S2CID   12295180.
  7. ↑ Kurimoto, Takuji; Yin, Yuqin; Habboub, Ghaith; Gilbert, Hui-Ya; Li, Yiqing; Nakao, Shintaro; Hafezi-Moghadam, Ali; Benowitz, Larry I. (11 September 2013). "Neutrophils express oncomodulin and promote optic nerve regeneration". Journal of Neuroscience. 33 (37): 14816–14824. doi: 10.1523/JNEUROSCI.5511-12.2013 . PMC   3771038 . PMID   24027282. S2CID   14640685.
  8. ↑ Aurora, Arin B.; Olson, Eric N. (3 July 2014). "Immune modulation of stem cells and regeneration". Cell Stem Cell. 15 (1): 14–25. doi: 10.1016/j.stem.2014.06.009 . PMC   4131296 . PMID   24996166.
  9. ↑ Kubin, Thomas; Pöling, Jochen; Kostin, Sawa; Gajawada, Praveen; Hein, Stefan; Rees, Wolfgang; Wietelmann, Astrid; Tanaka, Minoru; Lörchner, Holger; Schimanski, Silvia; Szibor, Marten; Warnecke, Henning; Braun, Thomas (4 November 2011). "Oncostatin M is a major mediator of cardiomyocyte dedifferentiation and remodeling". Cell Stem Cell. 9 (5): 420–432. doi: 10.1016/j.stem.2011.08.013 . PMID   22056139.
  10. ↑ Lilla, Jennifer N.; Werb, Zena (1 January 2010). "Mast cells contribute to the stromal microenvironment in mammary gland branching morphogenesis". Developmental Biology. 337 (1): 124–133. doi:10.1016/j.ydbio.2009.10.021. PMC   2787992 . PMID   19850030.
  11. ↑ Stefater, James A.; Lewkowich, Ian; Rao, Sujata; Mariggi, Giovanni; Carpenter, April C.; Burr, Adam R.; Fan, Jieqing; Ajima, Rieko; Molkentin, Jeffery D.; Williams, Bart O.; Wills-Karp, Marsha; Pollard, Jeffrey W.; Yamaguchi, Terry; Ferrara, Napoleone; Gerhardt, Holger; Lang, Richard A. (29 May 2011). "Regulation of angiogenesis by a non-canonical Wnt-Flt1 pathway in myeloid cells". Nature. 474 (7352): 511–515. doi:10.1038/nature10085. PMC   3214992 . PMID   21623369.
  12. ↑ Nahrendorf, Matthias; Swirski, Filip K.; Aikawa, Elena; Stangenberg, Lars; Wurdinger, Thomas; Figueiredo, Jose-Luiz; Libby, Peter; Weissleder, Ralph; Pittet, Mikael J. (26 November 2007). "The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions". The Journal of Experimental Medicine. 204 (12): 3037–3047. doi: 10.1084/jem.20070885 . PMC   2118517 . PMID   18025128. S2CID   6666039.
  13. ↑ Aurora, Arin B.; Olson, Eric N. (3 July 2014). "Immune modulation of stem cells and regeneration". Cell Stem Cell. 15 (1): 14–25. doi: 10.1016/j.stem.2014.06.009 . PMC   4131296 . PMID   24996166.
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