Endogenous Stem Cells in Homeostasis And Aging Part 3
Jul 11, 2023
7.1 Stem cell trafficking for tissue repair
Several growth factors and peptides, such as stromal cell-derived factor 1 alpha (SDF-1a), VEGF, G-CSF, and Substance-P, are known to mobilize bone marrow stem/ progenitors cells such as HSCs, EPCs, and BMSCs and facilitate tissue repair in well-defined animal models. The sequential events of the healing mechanisms have not been fully elucidated, but several studies strongly support the participation of mobilized EPCs and BMSCs, directly or indirectly, in tissue regeneration in situ [149–153]. Such small molecules or biologics could be efficiently and immediately used to treat patients in emergencies, such as following a stroke or acute myocardial infarction (AMI), by using patients’ stem cells in a stem cell mobilization and homing strategy.
Glycoside of cistanche can also increase the activity of SOD in heart and liver tissues, and significantly reduce the content of lipofuscin and MDA in each tissue, effectively scavenging various reactive oxygen radicals (OH-, H₂O₂, etc.) and protecting against DNA damage caused by OH-radicals. Cistanche phenylethanoid glycosides have a strong scavenging ability of free radicals, a higher reducing ability than vitamin C, improve the activity of SOD in sperm suspension, reduce the content of MDA, and have a certain protective effect on sperm membrane function. Cistanche polysaccharides can enhance the activity of SOD and GSH-Px in erythrocytes and lung tissues of experimentally senescent mice caused by D-galactose, as well as reduce the content of MDA and collagen in lung and plasma, and increase the content of elastin, have a good scavenging effect on DPPH, prolong the time of hypoxia in senescent mice, improve the activity of SOD in serum, and delay the physiological degeneration of lung in experimentally senescent mice With cellular morphological degeneration, experiments have shown that Cistanche has the good antioxidant ability and has the potential to be a drug to prevent and treat skin aging diseases. At the same time, echinacoside in Cistanche has a significant ability to scavenge DPPH free radicals and can scavenge reactive oxygen species, prevent free radical-induced collagen degradation, and also has a good repair effect on thymine free radical anion damage.
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Among the recombinant growth factors currently being produced at clinical grade, G-CSF, GM-CSF, VEGF, erythropoietin (EPO), and SDF-1a and their combinations are actively being studied based on their EPC and HSC mobilizing capacities to find a therapeutic modality for ischemic vascular diseases, such as AMI, ischemic limb disease, diabetic ulcer, and stroke. Other new candidate molecules, such as Substance-P (SP), which retains BMSC mobilization capacity, are also actively being studied in specific injury and disease animal models, such as AMI, stroke, diabetic ulcer, ischemic limb disease, rheumatoid arthritis, spinal cord injury (SCI), radiation-induced gastrointestinal damage, and corneal injury [153–161].
Some clinical studies have shown variable outcomes and more limited effects than expected. Their differential results could point to a fundamental issue of tissue regeneration in adults: tissue regeneration in situ requires recapitulation of developmental organogenesis. Thus, strategies need to be designed to fine-tune and regulate complex factors and cells, spatially as well as temporally, based on organogenesis and the traits of specific tissue injuries and patients. Specifically, the critical threshold concentrations of factors needed, locally and systemically, to initiate the trafficking of progenitor and stem cells to the target organ are largely unknown. In addition, accessory cellular components, such as myeloid cells and lymphocytes, might secrete auxiliary factors to control the inflammatory environment, remove dead cells to prepare a receptive tissue environment for incoming reparative stem cells, and facilitate specific local recruitment and positioning of circulating cells to reconstruct a well-defined tissue architecture. Those roles have not been considered in depth for tissue regeneration in situ.
Because a variety of age-related degenerative diseases could be considered to result from impaired tissue repair and recovery from the daily low-grade tissue damage that occurs from a variety of insults and infections throughout life, several endogenous factors, previously identified in stem cell self-renewal and trafficking and facilitation of tissue repair, could be candidates for anti-aging therapeutics. Some of them are highly correlated with the appearance of chronic disease and the aging phenotype, but proof of their roles in aging is a future topic for this field.
7.2 SP as a BMSC mobilizer and anti-inflammatory modulator: expectations for anti-aging
SP is an 11-amino acid neuropeptide secreted from the peripheral terminals of sensory nerve fibers, where it acts as a neurotransmitter or hormone. Subsets of neurons in the central and peripheral nervous systems [162], non-neuronal cells including macrophages and T lymphocytes, immune cells, and bone marrow stroma [163, 164] express SP and other structurally related peptides [165], all of which are encoded by the same gene, preprotachykinin-1 (PPT-1). Moreover, the SP receptor neurokinin 1 receptor is expressed on a variety of non-neuronal cells, such as BMSCs, chondrocytes, osteocytes, osteoblasts, osteoclasts, and mast cells [166–168]. SP mediates pain perception, neuro-immune modulation, cell proliferation, and enhanced proliferation and differentiation of endothelial cells, all of which are expected from its local action: direct nerve innervation and direct cellular contacts [169, 170]. In addition to its local action, intravenously injected SP works systemically to mobilize CD29. stromal-like cells (namely BMSCs) from the bone marrow to the periphery of blood, resulting in accelerated wound healing [153–161]. This new function of SP was initially identified as an injury-inducible messenger to trigger an endogenous wound healing mechanism, which recalls BMSCs mobilizing and homing to injured tissue.
In addition to its BMSC mobilizer function, SP enhances BMSC-mediated immune modulation at the late passage of BMSC by secreting TGF-b1. SP-induced BMSCs inhibit the activation of CD4? Jurkat T cells and decrease the secretion of IL-2 and IFN-c from T cells even in the presence of an activation factor such as LPS or CD3/CD28 antibodies [171]. Recently, SP’s novel function as a cytokine was identified; SP can directly polarize monocyte and macrophage phenotypes [172]. SP stimulates bone marrow-derived monocytes and macrophages to become tissue-repairing M2 macrophages through NK-1R signaling that expresses arginase-1 and secretes anti-inflammatory cytokine IL-10 [172]. Furthermore, SP stimulated the emigration of monocytes from the bone marrow and their infiltration to the injured tissue of a rat with SCI. In consequence, adoptively transferred SP-induced M2 macrophages reached the SCI lesion site and enhanced SCI functional recovery. Collectively, SP could have an integral role in tissue repair by recruiting reparative stem cells from the bone marrow, along with immune modulation systemically, locally, and in the bone marrow stem cell niche. It is a potential systemic factor regulating the proliferation, maintenance, and function of HSCs, BMSCs, and EPCs. Because SP level in the blood is low in diabetic patients and those with chronic cardiovascular disease, its role in the pursuit of successful tissue repair, especially in the case of acute tissue injury, might not be executed properly in the aged and people with those diseases. Thus, SP or its equivalent medication might be developed to recover a homeostatic basal level of SP and its injury-mediated induction mechanisms.
8 Conclusion and perspectives
This study has provided a comprehensive overview of the physiological homeostatic role of endogenous stem/precursor cells in the bone marrow (HSCs, BMSCs, and EPCs), along with their dysfunctions in a variety of chronic degenerative diseases and aging. Candidate systemic factors or small molecules that promote aging or rejuvenation, inflammation, stem cell trafficking, and tissue repair were reviewed from the perspective of age- or disease-related alterations, and possible pharmacological targets were elucidated for anti-aging therapeutics, retardation of senescence in ex vivo cell culture, and disease curing agents. Clinical studies of stem cell therapies have revealed many limitations of the current state of ex vivo cultured stem cell therapy. However, the factors stimulating stem cell self-renewal and retarding senescence mentioned in this review could offer a new pathway for stem cell therapy. Future studies using aging and age-related degenerative disease models might confirm those promising expectations.
Acknowledgments This work was supported by Grants NRF2016M3A9B4917320 from the Korean Ministry of Science, ICT and Future Planning, and HI13C1479 from the Korean Ministry of Health and Welfare to Dr. Y Son.
Compliance with ethical standards
Conflict of interest The authors have no financial conflicts of interest.
Ethical statement There are no animal experiments carried out for the article.
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