Endogenous Stem Cells in Homeostasis And Aging Part 2

 3.2 Oxytocin

Oxytocin is a circulating hormone and neuropeptide whose plasma level declines with aging. Muscle regeneration in young animals decreased when oxytocin was inhibited, and systemic administration of oxytocin enhanced aged muscle stem cell activation and proliferation by activating the MAPK/ERK signaling pathway, which increased muscle regeneration [14]. As an FDA-approved drug, oxytocin is considered a potential therapeutic and safe way to treat muscle aging. Moreover, oxytocin is released when hugging or bonding, which could also have anti-aging benefits.

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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3.3 Bursicon

Bursicon is an insect hormone and neuroendocrine hormone. Neurotransmitters released by nerve cells stimulate neuroendocrine cells to release bursicon into the bloodstream. Enteroendocrine cells in the gastro-intestine secrete bursicon, which binds to its receptor DLGR2 and inhibits epidermal growth factor (EGF) expression. The interaction of bursicon and DLGR2 in the Drosophila intestine maintains the quiescence of intestinal stem cells [52]. Bursicon is considered a local controller for the maintenance of intestinal stem cell homeostasis.

3.4 HGFA

HGF, a mesenchyme-derived heparin-binding glycoprotein, binds to the c-Met receptor, and that interaction regulates cell proliferation, cell survival, cell motility, and tissue regeneration through a tyrosine kinase pathway [53, 54]. Many previous studies showed that HGF activated the entry of quiescent satellite cells into the cell cycle. In 2014, Dr. Thomas Rando and his group reported that satellite cells and the extracellular matrix of damaged muscles secrete HGF, which promotes the entry of quiescent satellite cells from the G0 state to the GAlert stage through the mTORC1 downstream signaling pathway. GAlert cells are primed for proliferation and activation. Injury-induced secretion of a low level of HGF stimulates quiescent satellite cells to enter the GAlert stage, whereas prolonged injury-induced HGF signals quickly promote proliferation and activation for repair [55]. In 2017, the Rondo group showed that the systemic injection of HGFA induces proteolytic processing for HGF activation and stimulates the GAlert state in skeletal muscle stem cells. The administration of HGFA sufficiently achieved stem cell activation and tissue repair; thus, HGFA is proposed as a potential candidate for therapeutic applications in regenerative medicine [15].

3.5 CCL11

In 2011, Tony Wyss-Coray and his group reported that CCL11 level in blood plasma was increased in aged mice and humans. CCL11 inhibits neurogenesis and impairs learning and memory, so it was proposed as a circulating pro-aging factor using heterochronic parabiosis experiments [7]. The same group has struggled to determine the systemic factors associated with aging and tissue degeneration using a proteomic approach. Sixty-six cytokines,  chemokines, and secreted signaling proteins were measured in the plasma of normal aging mice using standardized, multiplex sandwich enzyme-linked immunosorbent assays (ELISAs; Luminex). Among those 66 proteins, CCL2, CCL11, CCL12, CCL19, haptoglobin, and b2-microglobulin (B2M) increased in aged mice and young heterochronic parabiosis mice. CCL11 is a chemokine involved in allergic responses that have not been reported as an aging factor. However, a high level of CCL11 is detected in cannabis users and people suffering from schizophrenia triggered by cannabis [56]. Although CCL11  does seem to be an aging-associated systemic molecule,  exactly how it promotes the aging process needs further study.

3.6 B2M

The Wyss-Coray and Saul A Villeda group also reported B2M as a systemic pro-aging factor that impairs cognitive function and neurogenesis in mice [57]. B2M is a component of major histocompatibility complex class I (MHC I) molecules, which are elevated in the blood and hippocampus of aging humans and mice. Exogenous injection of B2M systemically or locally to the hippocampus impairs hippocampal-dependent cognitive function and neurogenesis in young mice, and the absence of endogenous B2M in B2m-/- mice eliminates age-related cognitive dysfunction and enhances neurogenesis in aged mice [57]. Furthermore,  an increased systemic level of soluble B2M has been detected in the cerebrospinal fluid of patients with HIV dementia [58, 59] or Alzheimer’s disease [60]. The strong association between systemic B2M level and cognitive function decline suggests B2M is a strong potential pro-aging systemic factor. Although the Wyss-Coray and Villeda group has not yet isolated any anti-aging factors from young plasma, they did find that young blood reversed age-related impairments in cognitive function and synaptic plasticity of old mice [61]. In addition, they have conducted a clinical trial in humans that used a series of plasma transfusions from young donors (\30) to older Alzheimer’s patients [62]. There is a therapeutic promise for rejuvenating factors that could turn back the clock for aging people, but such factors are only a starting point to understanding aging.

4 Stem cell niche as a positive or negative  regulator

Within the bone marrow, HSCs, BMSCs, and EPCs exist in a tightly controlled microenvironment, a niche, that contributes to the control of quiescence, proliferation, self-renewal, and differentiation. This stem cell niche is composed of a specialized population of cells that includes soluble factors such as cytokines, chemokines, and growth factors and produces chemical, physical, and mechanical signals for oxygen tension, extracellular matrices, shear forces, temperature, surrounding pH, and monoatomic ions,  all of which regulate stem cell behavior. This section considers how many age-related changes in these cellular or microenvironmental components of the niche affect the function of stem cells or the stem cell niche itself.

4.1 HSC Niche in Young and old bone marrow

The stem cell niche for HSCs, which contains many cellular components and their secretions, regulates HSC  homeostasis and trafficking using distinct mechanisms. BMSCs, endothelial cells of arterioles/capillaries/sinusoids, osteoblasts, the sympathetic nervous system, T cells,  and macrophages are all recognized as positive regulators,  whereas adipocytes and osteoclasts are generally known to be negative regulators (Fig. 4). Nestinmid PDGFa? CD51?  perivascular cells reside near HSCs and the adrenergic nerve and maintain the quiescence of HSCs by secreting cytokine chemokine (C–X–C motif) ligand 12 (CXCL12)  and stem cell factor (SCF) [63]. CXCL12-abundant reticular (CAR) cells, which are Nestin? Mx-1? Lepr?Prx-1? MSC-like cells near the endosteum, regulate HSC self-renewal, proliferation, and mobilization [64]. Endothelial cells on the arteriole and sinusoid support HSCs by secreting FGF, EGF, DLL1, IGFBP2, ANGPT1, DHH,  pleiotrophin, and Jagged-2 [12, 65, 66].

The endosteal stem cell niche contains a specialized hypoxic immune privilege site to protect HSCs from inflammatory insult. Approximately 80% of Lin-Sca1?- KIT? CD41-CD150?CD48- HSCs are found close to the endosteal niche on the bone surface, and only 20% of HSCs reside near the central vein of the bone center [12]. In the endosteal niche, specialized osteoblastic cells (SNO cells)  provide quiescent signals for HSC maintenance. SNO cells and HSCs form a cell–cell junction with N-cadherin and induce b-catenin-mediated PTEN activation that blocks PI3K/Akt/mTOR-induced cell cycle entry. Both SNO cells and HSCs form an adhesive junction between VCAM and VLA4 and between fibronectin and VLA5. SNO cells inhibit HSC activation, differentiation, and apoptosis by providing BMP, Jagged, and Ang-1 [67]. Treg cells, which accumulate on the endosteal surface, provide immune suppression privileges to HSCs by secreting the anti-inflammatory cytokine IL-10. HSCs seem to reside within 20 lm of CD4.CD25?FoxP3? Treg [68]. Sympathetic nerve systems in the bone marrow also protect HSCs by secreting TGF-b activator from non-myelinating Schwann cells, which interacts with the TGF-b receptor on the HSC  surface to activate the phosphorylation of SMAD2/3 signaling and cause the maintenance and quiescence of HSCs [69]. Adrenergic nerve and Nestin? BMSCs highly express HSC maintenance genes, including CXCL12, ANGPT1, Kit ligand, and VCAM-1, whereas activation of the adrenergic receptor downregulates that gene expression [70].

Recently, researchers have found that macrophages play an important role in the maintenance of LT-HSCs, whose depletion by granulocyte–colony-stimulating factor (GCSF) activates a sympathetic nerve to secrete norepinephrine, which causes HSC egress into the blood [71]. CD82/KAI1, which is highly expressed on the surface of LT-HSCs, promotes LT-HSC quiescence by interacting with DARC (CD234) on the macrophages following the TGF-b1/Smad3 signaling pathway [72]. Low CD82  expression is associated with tumor progression. Endothelial DARC is known to induce the senescence of CD82.  tumor cells [72]. a-SMA?COX-2? monocytes and macrophages maintain hematopoietic stem progenitor cells (HSPCs) through the production of prostaglandin E2, which inhibits the production of ROS in HSPCs by limiting stromal-cell expression of the chemokine CXCL12 [73]. CD169? macrophages in bone marrow are distinct from the M1/M2 macrophage subtypes and express CD206, VCAM- 1, and CCL22 [74]. CD169 (Sialo-adhesion) is a cell adhesion molecule present on the surface of macrophages. CD169? macrophages constitute approximately 2.6% of all bone marrow cells, support the HSC niche, and promote HSC retention with Nestin. BMSCs and b-adrenergic neurons in the bone marrow [75].

What negative regulators affect the HSC niche? After irradiation and in advanced aging, BMSCs tend to differentiate into adipocytes and fill the marrow space, which is understood to inhibit HSC function. Inhibiting adipogenesis enhances bone marrow recovery [76]. Also, in 2017, Ambrosi et al. [77] used a competitive repopulation assay following lethal irradiation and reported that adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell–based hematopoiesis and bone regeneration. As part of that mechanism, they proposed that the bone-resident adipocytic lineage produced an excessive amount of dipeptidyl peptidase-4 (DPP-4), a target for diabetes therapies that could deteriorate the HSC niche. Another dispensable type of cell for a healthy HSC niche is the bone-degrading osteoclast. In an osteoprotegerin-defi- client model mouse, osteoclasts degrade the endosteal niche and induce HSC mobilization [78, 79]. In aging bodies, the exhaustion of niche-supporting cells and the upregulation of adiposity in bone marrow can occur at the same time,  which deteriorates normal HSC homeostasis.

4.2 BMSC/EPC niche

For decades, BMSC research has emphasized the pivotal role of BMSCs in wound healing and tissue regeneration. However, the current understanding of the cells and signals that constitute the BMSC niche is very limited. BMSCs are generally mixtures of progenitor cells in the bone marrow. CD31? EPCs are known to be closely neighbored by BMSCs and enhance the self-renewal capacity of BMSCs in vivo and in vitro [80]. Specifically,  the fibronectin in EPCs, a component of the extracellular matrix for the HSC niche, is known to activate the integrin in BMSCs and promote self-renewal [81, 82]. EPCs are a  major biological component of the BMSC niche and affect the biological processes of BMSCs. IGF-1/IGF-2 bind to IGF-1R/IGF-2R on BMSCs and increases proliferation and self-renewal [83]. CXCL12 enhances BMSC colony-forming capacity, which is promoted by activation of the  b3-adrenergic neuron and followed by promotion of EPC colony-forming potency [84].

5 Epigenetic changes in stem cells during aging

During the past decade, accumulating evidence has supported changes in epigenetic information during aging in both stem cells and somatic cells. Epigenetics refers to all heritable changes in gene expression that are independent of DNA sequencing. Epigenetic modifications in the genome and DNA-associated proteins are required for the maintenance of biological states such as cell identity, with particularly extensive implications for stem cells. Different types of epigenetic changes are encoded within the epigenome, including reduced core histones, histone posttranslational modifications, structural and functional variants of histones, DNA methylation, chromatin remodeling, and altered noncoding RNA expression during both aging and senescence. Those epigenetic changes cause aberrant gene expression, telomere shortening, and genomic instability [85]. Histone modifications such as methylation, phosphorylation, ubiquitination, and acetylation can act separately or synergistically to regulate gene expression through changes in chromatin structure. Histone methylation is a complex epigenetic event that leads to different transcriptional outputs depending on the lysine (K) residue, such as K4, K9, K20, K27, K36, and K79. For instance, histone H3 methylated on K4 or K36 is generally associated with active genes, whereas methylation at K9  and K27 is mostly linked to gene repression.

DNA methylation is a relatively stable epigenetic modification restricted to cytosine residues in the CpG dinucleotides by DNA methyl transferase enzymes (DNMTs). Chromatin remodeling is a protein-mediated event that leads to chromatin rearrangements and helps access the nucleosomal DNA using SWItch/sucrose non fermentation (SWI/SNF), polycomb group (PcG), and Trithorax group (TrxG) proteins. Non-coding RNAs,  including microRNAs (miRNAs, * 20 nucleotides) and long-non-coding RNAs (lncRNAs, * 200 nucleotides),  which are not translated into proteins, participate in the posttranscriptional regulation of gene expression.

5.1 Epigenetic Research in diverse species  and progeria model

Invertebrates are popular models for aging studies because they have short lifespans and provide easy genetic and environmental manipulation. In addition, vertebrate models such as mice, rats, and zebrafish are usually used. In yeast,  removing the chromatin remodeler SWI/SNF (ISW2)  demonstrated an extension of the replicative lifespan and mimicked caloric restrictions through changes in the nucleosome positioning critical for regulating gene expression [86]. In the past 10 years, histone methylation regulators such as H3K4me3, H3K27me3, and H3K36me3  were found to be involved in regulating the lifespan of C. elegans [87–89]. Additionally, increased levels of key metabolites, such as acetyl CoA, and increased global histone acetylation, including acetylated lysine 12 on histone H4 (H4K12ac), were confirmed during the aging process. H4K12ac mutation extended the lifespan of Drosophila [90]. Mainly in metabolism and aging, the mammalian sirtuin protein family (SIRT1–SIRT7) regulates mitochondrial function and enhances stem cell survival. Sirtuins deacetylate histones and several transcriptional regulators in the nucleus in cellular compartments [91]. In mice, studies on the causes of aging have been conducted by examining premature aging (progeria), such as in Werner’s syndrome and Hutchinson–Gilford progeria syndrome (HGPS), genetic disorders that lead to a shortened lifespan and occur by recessive mutation of the Lamin A gene, which leads to chromatin modification,  metabolic defects, stem cell exhaustion, cell cycle deregulation, and inflammation [92, 93].

5.2 Epigenetic changes in aged stem cells

Modifications to DNA/histones and non-coding RNA-mediated mechanisms are epigenetic events that play important roles in the regulation of stem/progenitor cell functions by changing the chromatin structure. Epigenetic changes in adult stem cells are critical during aging because they alter the function, clonal composition, and lineage fate of stem cells which have been regulated by intrinsic and extrinsic epigenetic modifiers. The activating H3K4me3 mark and the repressive H3K27me3 mark are bivalent domains thought to affect developmental gene expression. These bivalent domains also allow timely activation and repression in the absence of differentiation signals [94]. The H3K27me3 mark is essential for maintaining the repressed form of these genes, whereas the H3K4me3/1 mark could lead to activation upon induction of differentiation through external signals.

5.3 Epigenetic changes of HSCs in the aging  and stem cell hierarchy

Interdependency between histone modification and DNA  methylation could be related to HSC aging. In stem cells,  the repressive H3K27me3 mark in young and aged HSCs,  together with two chromatin marks related to active transcription, H3K4me3, and H3K36me3, has been epigenetically profiled by ChIP-seq. The presence of H3K4me3  during HSC aging could increase self-renewal in old HSCs [95]. In contrast, in adult skeletal muscle stem cells or satellite cells, the presence of H3K4me3 marks showed little or no difference in young and old mice [96]. This conflicting result could suggest that repressive H3K4me3  marks are the cause of other mechanisms, not transcription suppression, among different stem cells. Additionally, HSCs are connected to the loss of the H4K16ac activation mark during aging [27]. Moreover, Kdm3a and Kdm5b  have been reported to regulate stem cell aging because their levels decrease during the aging process [97, 98]. Knockdown of the lysine demethylase Kdm5b (Jarid1b)  enhanced the in vitro expansion of HSCs and their in vivo lymphomyeloid differentiation potential [99]. In addition,  histone methylation of H3K27me3 is a key regulator of hematopoiesis. Recent studies have reported that young HSCs showed a low level of methylation in the genomic region associated with blood cell production, whereas aged HSCs showed DNA hypermethylation in the genomic regions associated with the lymphoid/erythroid lineages [100].

Epigenetic regulators, such as the ten-eleven translocation (Tet) enzymes that regulate demethylation and the DNMTs that cause the methylation of CpG motifs, appear within the HSC compartment during aging. Different expression levels have been revealed for both Tet2 and DNMTs in young and old HSCs [95]. A recent mouse study demonstrated that Tet2 loss causes myeloid transformation and malignancies [101]. DNMT1 plays a role in maintaining methylation, and DNMT1 deficiency in HSCs demonstrated myeloid skewing and a defective self-renewal process [102, 103]. Moreover, the lost function of DNMT3A and DNMT3B caused a lack of HSC differentiation [104].

LT-HSCs express an evolutionarily conserved miRNA cluster that includes miR-99b, let-7e, and miR-125a. miR- 125a is involved in increasing the number of HSCs in vivo by eightfold and enriches lymphoid-balanced HSCs [105, 106]. The lncRNA Xist is essential for HSC survival; Xist-deficient HSCs cause abnormal hematopoiesis and age-dependent loss [107].

5.4 Epigenetic changes of BMSCs during ex vivo cell expansion and differentiation

The epigenetic mechanisms of BMSCs are relatively well investigated because of their therapeutic applications in regenerative medicine. Epigenetic changes help regulate the expression of several genes associated with the stemness of BMSCs and the differentiation of diverse cell types containing osteocytes, chondrocytes, or adipocytes.

Li et al. [108] compared the epigenetic modifications of histone H3 acetylation in early- and late-passage BMSCs. Histone H3 acetylation is an essential event in regulating BMSC aging and differentiation. For instance, the H3 acetylation level coincides with gene expression levels such that K9 and K14 histone H3 acetylation occurs in various genes, including Oct4, Sox2, TERT, ALP, and Runx2, in the late passage. Histone deacetylase inhibitors promote apoptosis and senescence in human BMSCs [109]. DNA  methylation levels decline during BMSC senescence, and inhibition of DNMT1 and DNMT3b promotes cellular senescence in umbilical cord blood BMSCs through increased expression of p16INK4A and p21CIP1/WAF1 [110].

Recently, research has examined the epigenetic mechanisms that regulate BMSC differentiation. In the osteogenesis of BMSCs, chromatin hyperacetylation, histone methylation of H3K4me3 at the promotor of the HOXA10  gene, and demethylation of H3K27me3 contribute to the osteogenic determination of BMSCs by inducing activation of the osteogenic transcription factor Runx2 [111, 112]. Histone methylation of H3K4 and H3K36 at the AP-2a  gene increases the osteogenic and odontogenic potential of BMSCs [113]. The acetylation of H3 and H4 at the osteocalcin gene or the acetylation of H3K9 induces osteogenic differentiation of BMSCs [114, 115]. DNA  methylation at the promoter of osteopontin decreases during the induction of osteogenic differentiation in BMSCs [116]. In addition, miR-27a, miR-489, miR-204, and miR- 138 decrease osteogenic differentiation by reducing the expression of alkaline phosphatase, Runx2, or osterix [117, 118], and miRNA-20A, miR-148b, miRNA-2861,  and miR-335 induce osteogenic differentiation by activating BMP/Runx2 [108, 119, 120].

During BMSC chondrogenesis, histone modifications and non-coding RNAs could be involved, rather than DNA  methylation. Genes transcriptionally upregulated during chondrogenesis are marked by H3K36me3 of the gene body, H3K4me3 and H3K9ac of the 50 ends of genes and promoters, and H3K4me1 and H3K27ac [121]. The expression of miR-130b, miR152, miR28, and miR26b  increases in chondrogenesis [122], and miR-145 expression decreases, which causes increased expression of SOX9 [123]. Moreover, miR-29 induces chondrogenesis by regulating FOXO3A [124], and miR-574-3p inhibits chondrogenesis [125].

Only a few studies have been conducted on BMSC  adipogenesis. Histone methylation of H3K4me2 occurs at the promotor of adipogenic genes such as adiponectin,  glut4, and leptin [126]. In addition, the methyltransferase enhancer of zest 2 (EZH2) induces adipogenesis by trimethylation of H3K27, but the demethylase KDM6A  causes osteogenesis by removing the methylation of H3K27me3. Knockdown of EZH2 increased osteogenesis,  whereas knockdown of KDM6A increased adipogenesis [127].

5.5 Epigenetic Changes of EPCs in Angiogenesis and Aging

Interest in EPCs has risen because of their potential in stem cell therapies for ischemic injuries to facilitate revascularization. Epigenetic regulators that increase the vascular repair function of endothelial progenitor cells offer potential breakthroughs for clinical application strategies. The use of epigenetic drugs to reverse those epigenetic marks and enhance revascularization is being studied.

In histone modification of EPCs, the full extent of bivalent genes between the activating H3K4me3 mark and the repressive H3K27me3 mark is unclear. H3K4 methylation is essential for angiogenesis because lysine-specific demethylase 1 (LSD1) suppresses metastasis and angiogenesis by inducing H3K4 demethylation [128]. EZH2 is a  negative regulator of endothelial cell differentiation that is overexpressed in cancer cells, represses differentiation genes, and maintains stemness through the deposition of repressive H3K27me3 marks [129]. H3K36me3 methyltransferase is required for vascular development, endothelial cell differentiation, and function [130]. Epigenetic changes in EPCs with increased H3K4m3 and reduced H3K9me3 induce the secretion of pro-inflammatory cytokines such as MCP-1 and IL-6 and impair the angiopoietic phenotype, which leads to increased risk for cardiovascular disease [131].

The contribution of DNA methylation/demethylation to endothelial gene regulation remains poorly understood. Recent studies have reported repressive H3K27me3 and DNA methylation marks in eNOS promoters in early EPC,  which can be reversed in hypoxic conditions to increase eNOS expression and thus increase endothelial recruitment and differentiation [132]. The histone deacetylase enzyme HDAC1 is also recognized to have an essential part in the inhibition of endothelial proliferation and differentiation [133].

Research about the non-coding RNAs in EPCs has progressed steadily. miR-21, miR-27a, miR-27b, miR-126,  and miR-130a are expressed in EPCs but are decreased in circulating EPCs. In diabetic patients, EPCs express low levels of miR-126 and miR-130. Inhibiting miR-126  decreases proliferation and migration, and inhibition of  miR-130 represses EPC differentiation [134, 135]. miR-10A* and miR-21 progress EPC aging, and blocking those miRNAs induces an anti-aging process, enhancing angiogenic capacity [136].

6 Inflammation and aging

Inflammation is a pivotal pathophysiological process that protects bodies from infection and repairs injuries. As people age, they experience many infections and diseases and build an antigenic burden, which can induce unbalanced inflammatory circumstances. During aging,  increased adipose tissue caused by a high glucose/fat diet,  decreased sex hormones, smoking, and stress combine to cause chronic, low-grade, systemic inflammation. The so-called inflammaging [8, 9] gives rise to age-related diseases such as cardiovascular disease, cancer, diabetes, and osteoporosis [137]. Many studies about the relationships between aging, inflammation, and disease have been conducted. The levels of pro-inflammatory cytokines and chemokines increase in aged people. IL-6, TNF-a, IL-1b,  and C-reactive protein (CRP), which is released in the liver in response to IL-6, all increase in the serum of older humans [137]. Pro-inflammatory markers are considered to be predictors of age-related diseases such as cardiovascular disease, cancer, diabetes, osteoporosis [137], and neurodegenerative disorders such as Alzheimer’s disease [138]. In addition, HIV-infected patients can experience premature aging through chronic inflammation and immune-senescence, which causes T-cell dysfunction and progenitor cell exhaustion [139]. Chronic inflammation causes oxidative stress, mitochondrial dysfunction, age-related diseases, myeloid-biased differentiation, telomere shortening, epigenetic modifications, etc. [140]. It is still a  mystery whether inflammation is a cause or outcome of aging.

6.1 Inflammation and stem cell aging

Aged stem cells show downregulation of colony-forming units and growth factor/cytokine/chemokine release. Quiescence and retention of HSCs are both supported by vascular endothelial growth factor (VEGF), TGF-b1, and IL-10, which all function as anti-inflammatory signals [12]. However, in aged bone marrow, those factors decrease, and inflammatory signals increase, which induces immunogenicity. Inflammatory signals act as emergency calls for HSCs. Within 1 h of an infection induced by E. Coli-derived LPS injection, LPS reaches the bone marrow,  interacts with TLR4 on HSCs, and causes proliferation [10, 141]. IFNs such as IFN-a and IFN-c act directly on HSCs to move quiescent HSCs into the proliferation and differentiation stages. Under stressed conditions, such as a bacterial or viral infection, cytotoxic CD8? T cells and HSCs secrete IFN-c, which causes the expression of the myeloid transcription factors C/EBPa and Runx1 in HSCs [142], and CD4. T cells produce IFN-c through the TLR/ MyD88 pathway [143]. Activated BMSCs and HSCs produce IL-1, IL-6, TNF-a, G-CSF, and granulocyte–macrophage colony-stimulating factor (GM-CSF) [141], which lead to myeloid-biased differentiation, mobilization, and proliferation [141–144]. These results show that anti-inflammatory therapies that control the inflammatory signals in the bone marrow microenvironment could modulate stem cell fate.

6.2 Anti-inflammatory control of stem cell aging

Ten years ago, Bente K Pedersen published a paper titled ‘‘Anti-inflammation—just another word for anti-aging?’’ [145]. He reported that, in age-related and chronic inflammatory diseases such as atherosclerosis, diabetes,  cardiovascular disease, Alzheimer’s disease, and cancer,  the administration of non-steroidal anti-inflammatory drugs at systemic concentrations would reduce occurrence rates and counteract the inflammation-induced inhibition of protein synthesis in old people [145]. For instance, salsalate, an anti-inflammatory drug that inhibits NF-jB and a  dimer of salicylic acid, reduces systemic inflammation and prevents type 2 diabetes in obese adults [146]. Dr. Thomas von Zglinicki and his group studied low-grade inflammatory nfkb1-/- knockout mice, which age prematurely and have decreased regeneration capacity in the liver and intestine [147]. The kb-/- fibroblasts increased NF-kB, COX-2, and ROS through a feedback loop, causing DNA  damage such as telomere dysfunction and senescence. However, anti-inflammatory or antioxidant administration recovered the tissue regeneration [147]. In addition, his team measured the blood cell numbers, metabolism, liver and kidney function, telomere length, and level of inflammation of Japanese centenarians [148]. They reported that centenarians showed longer telomere length than the general population and also that inflammation is an important cause of aging in very old humans. Immune modulation and safer anti-inflammatory medicines have the foremost potential and are good candidate therapies to promote a  healthy lifespan [148].

7 Stem cell self-renewal and trafficking:  expectations for tissue repair and anti-aging

Stem cells with differential potentials, such as adult stem cells, embryonic stem cells, and induced pluripotent stem cells, are expected to be used to repair tissue loss and injury for functional recovery from a variety of degenerative diseases and trauma. Several critical issues, such as well-controlled lineage-specific differentiation, mass production of stem cells, high cost of ex vivo cell culture, low engraftment at transplantation site, and short half-life of the therapeutic cells, have to be resolved for clinical applications to advance. On the other hand, endogenous adult or tissue stem cells reserved in the tissue and organs of the body could be used for tissue repair without elaborate ex vivo cell culture if small molecules or growth factors that regulate stem cell self-renewal and trafficking can be identified.

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