The Interaction And Coordination Between Stem/progenitor Cells And Kidney Microenvironment
Mar 22, 2022
Contact: joanna.jia@wecistanche.com / WhatsApp: 008618081934791
PART Ⅲ: Stem/progenitor cell in the kidney: characteristics, homing, coordination, and maintenance
Jiewu Huang, Yaozhong Kong, Chao Xie, and Lili Zhou
CLICK HERE TO PART Ⅱ
After kidney injury, kidney cells could release a variety of growth and inflammatory factors, including insulin-like growth factor-1 (IGF-1), hepatocyte growth factor (HGF), basic fibroblast growth factor(bFGF), and vascular endothelial growth factor (VEGF), to promote tubule degeneration and kidney repair [112-115]. Moreover, it has been reported that renal stem/progenitor cells, resident MSCs, and BMDCs could self-renew, migrate into the injured area, and then differentiate to aid tissue re-pair [11,18,21,73,78](Fig.2).
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Micro inflammation
Recruitment of stem/progenitor cells
The stromal-derived factor-1(SDF-1)/chemokine(C-X-C motif) receptor 4(CXCR4) axis plays an important role in the migration of BMDCs and renal stem/progenitor cells[116,117].SDF-1, a main regulator of migration and mobilization for BMDCs[118], is upregulated in the surrounding resident cells of the necrotic area [14,119, 120]. CXCR4 and CXCR7, the receptors of SDF-1, are highly expressed in renal stem/progenitor cells[119,121]. CXCR4 is essential for migration, and CXCR7 plays a significant role in adhesion to endothelial cells and the survival of kidney stem/progenitor cells[119]. CXCR4 and CXCR7 are also expressed in BMDCs [118,122-125]. Studies also show that the upregulation of SDF-1 in injured areas increases the expression of CXCR4 in BMSCs[126,127]. Moreover, the role of CXCR4 or CXCR7 in BMSCs is similar to that in renal stem/progenitor cells [128]. A study shows that the SDF-1/CXCR4 axis plays an important role in BMSC migration as well as in survival and cytokine secretion in the injured area by activating the Akt and Erk pathways [127].
CD44-hyaluronic acid (HA)interaction also plays an important role in the migration of BMDCs to the injured area [129-132]. HA is the major ligand of CD44, which is expressed in BMSCs, will increase after tissue injury in both chronic and acute kidney injury [129,130,132]. A study shows that CD44-HA interaction also plays an important role in the stimulatory effects of SDF-1 on BMDC migration [132]. In addition, osteopontin is also upregulated after kidney injury [133,134], which promotes the expression of its receptor integrin β1 in BMSCs, and leads to the migration of BMSCs in a dose-dependent manner [117,135]. Moreover, it has been found that CD44v6, another receptor of osteopontin, which is also expressed in BMSCs, may also play an important role in the migration of BMSCs to the injured kidney[135,136]. The capacity of BMSCs to reshape themselves, depending on their stiffness, is related to the structure of the cytoskeleton and significant for migration due to the physical ability when crossing tissue and vessels[137]. Osteopontin also lowers the expression of cytoskeleton proteins through FAK/ERK1/2 pathway, contributing to BMSC migration by reducing cell stiffness [117].
Besides, growth factors and proinflammatory cytokines released by the injured area, including bFGF, VEGF, platelet-derived growth factor (PDGF), transforming growth factor β1(TGF-β1), IGF-1, HGF, tumor necrosis factor-alpha (TNF-α)[138-140], and interferon-gamma (IFN-y)[140], also play a significant role in the migration of BMSCs [117,141]. However, the sustained up-regulation of PDGF, a powerful growth factor in BMSC recruitment and tissue repair in the injured kidney [142], could also lead to renal fibrosis by activating myofibroblasts, mesangial cells, or smooth muscle cells [143]. It has also been found that FGFs, a factor playing an important role in stem cell self-renewal [144], are released after kidney injury to be requisite for the recruitment of kidney stem/progenitor cells and maintenance of cell adhesion [145].
Fig.2 After kidney injury, the microenvironment would turn to be inflammatory, hypoxic, and immunostimulatory. The proinflammatory microenvironment induced by neutrophil granulocyte and mononuclear macrophage infiltration leads to the massive release of injurious factors such as TGF-β, IFN-y, IL-6, and so on. This will recruit stem/progenitor cells through the interaction between SDF-1 and CXCR4/7, HAosteopontin and CD44, and others. In addition, the insufficient oxygen supply caused by ischemia and increase in oxygen consumption in the disease state would certainly result in a hypoxic microenvironment. This would aid in the recruitment and differentiation of stem/progenitor cells and induce the production of lots of angiogenesis factors in these cells to facilitate tissue repair. The immune responses include the activation of B cells. T cells, NK cells, and dendritic cells construct the local immune microenvironment to affect the stem/progenitor cell-induced tissue repair. Overall, the various factors in the local microenvironment build up an intricate network to cooperatively assist stem/progenitor cell functions and finally promote stem/progenitor cell-dependent tissue repair through their beneficial effects on angiogenesis, anti-inflammation, immunoSuppression, and others
Anti-inflammation and tissue repair of stem/progenitor cell
Differentiation is not the only mechanism by which renal stem/progenitor cells or BMDCs repair the injured kidney; this is also accomplished through a paracrine mechanism. It has been found that extracellular vesicles (EVs) could form an important part of the paracrine system. EVs are small, lipid membrane-enclosed subcellular structures carrying biomolecules of proteins, lipids, nucleic acids, and sugars. They are released from cells into the extracellular environment and even could reach remote areas. EVs include exosomes, microparticles, or microvesicles [146-149]. Notably, kidney stem/progenitor cells could secrete IL-15, endothelial growth factor, HGF, leukemia inhibitory factor, inhibin-A, decorin, VEGF, and recombinant human bone morphogenetic protein (BMP)-7 through direct release or through shuttling mRNA or miRNA using EVs, to repair the renal injury, alleviate inflammation, and retard fibrosis[14,150-152]. A study shows that the effects of EVs of kidney stem/progenitor cells may primarily depend on the shuttling of mRNA or miRNA, because after treatment with RNase, EVs are not effective in improving kidney function and aiding recovery. Meanwhile, physiological doses of RNase cannot degrade the RNA in the EVs, but high-dose can [152].
Besides, BMSCs also play a significant role in anti-inflammation and facilitating tissue repair after kidney injury. Several studies have suggested that the main protective mechanism of BMSCs in kidneys is through paracrine action rather than differentiation [153-156]. They performed the study using the Y chromosome as a marker of donor BMSCs; they could not find BMSCs within the tubules in that infusion of BMSCs, and BMSCs were rare in the renal interstitium. However, they found kidney failure was ameliorated [155]. Moreover, conditioned medium from cultured BMSCs not only induces migration and proliferation of renal epithelial cells and greatly alleviates proximal tubular cell death in vitro, but also inhibits kidney injury after intraperitoneal administration [155]. BMSC administration downregulates TGF-β, IFN-y, IL-6, and IL-1β expression and further represses inflammation and fibrosis through the direct secretion of repairing cytokines or release of EVs [14, 42,153,157-159]. The administration of BMSCs also inhibits the expression of apoptosis-related proteins such as Bax, cytochrome c, and caspase-3, increases the activity of superoxide dismutase(SOD), and regulates autophagy-associated proteins such as Beclin l, PINK1, Parkin, p-Parkin, LC3B, and MAPK signaling-related proteins to decrease apoptosis and oxidative stress[160-163]. However, one study also shows BMSC could differentiate into myofibroblasts upon long-term stimulation by TGF-β[164].
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Hypoxia and angiogenesis
Hypoxia is one of the most common features of tissue injury [159]. A study shows that a hypoxic microenvironment could enhance the migration of BMSCs[141]. The expression of SDF-1 in the kidney is increasing after ischemic or hypoxic injury[120,128, 165]. Besides, hypoxia also increases the expression of CXCR4 in BMSCs[128]. It indicates that hypoxia may play a significant role in the recruitment of stem/progenitor cells into the injured kidneys by the SDF-1/CXCR4 axis. After renal stem/progenitor cells migrate into the injured area, the microenvironment of low-oxygen tension induces them to proliferate and produce erythropoietin to limit renal fibrosis via activating the hypoxia-inducible factor-2α(HIF-2α) axis by prolyl hydroxylase [76, 166, 167]. Erythropoietin could also increase the expression of SDF-1 in the kidney [168]. Hence, the interaction between the hypoxic microenvironment and renal stem/progenitor cells may form a positive cycle for recruiting stem/progenitor cells and subsequent repair.
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Kidney-resident MSCs could release the EVs carrying VEGF, bFGF, and IGF-1, the proangiogenic factors, to contribute repair through their anti-apoptotic and angiogenic effects [152,169,170]. Hypoxic culture of MSCs could induce the secretion of these pro-vasculogenic fac-tors [159], such as IGF-1, VEGF,bFGF, HGF,and thymosin β4 (TB4), to facilitate tissue repair and ultimately promote kidney protection [51,113,154,171-174]. Similar to kidney-resident MSCs, studies have shown that BMSC-derived EVs could also protect against kidney injury through anti-apoptotic and angiogenic effects [159, 175]. The biological effects of BMSC-derived EVs may mainly depend on the contained RNA, including mRNA and microRNA because RNase could abolish the effects of EVs[176]. The EVs, as a tool of transportation, can shuttle the specific subset of cellular RNAs of BMSCs, especially RNAs associated with transcription and proliferation, to modulate energy metabolism and cellular pathways of recipient cells [35, 169,176-178]. Studies have shown that more EVs are engrafted into the injured kidney than the normal after injection. Furthermore, the majority of EVs are taken up by tubular epithelial cells and peritubular capillaries, but some also by glomeruli [169]. However, the underlying mechanism is still a mystery.
A study shows that EPCs could be mobilized into glomeruli after kidney injury. They would self-renew, differentiate into glomerular endothelial cells, and ex-press hypoxia-inducible factor 1(HIF-1), the key transcription factor driving VEGF expression [54,179], to rebuild the glomerular capillary structure [89, 180]. Moreover, EPCs can also enhance renal growth factor expression and retard oxidative stress in the ischemic kidneys [181]. Like MSCs, EPCs can also ameliorate kidney in-jury and enhance angiogenesis through EVs release for delivering miRNA, because some researches show the renoprotective effects of EVs are lost after treatment with RNase or specific miRNA-antagomirs [182-184].
Local immune response
Studies have shown that after kidney ischemia injury, mature dendritic cells are increased. As an antigen-presenting cell, dendritic cells would induce T cell proliferation and migration to inspire the immune response [185].T cells, especially CD4*-T cells, are an important source to persist inflammation in CKD patients [16,186,187]. Abnormal activation of T cells leads to a release of proinflammatory cytokines such as TNF-α and IFN-γ【186】， which play an important role in the recruitment of BMSCs [138-140]. B cells may also play a role in kidney injury. A study shows that B cell deficiency plays a protective role in renal IRI mice [185]. The network of dendritic cells, T cells, and B cells construct the local immune microenvironment to affect the stem/progenitor cell-induced tissue repair.
Studies show that MSCs and renal stem/progenitor cells in papilla exhibit the capacity of immunomodulation [15,16,74]. They can greatly reduce T cell proliferation through cell-cell contact and inhibit the stimulatory effects of dendritic cells on T cells and the secretion of prostaglandin E2, an anti-inflammation fac-tor [15, 16,188,189].BMSCs also exert an inhibitory effect on the proliferation of T cells and natural killer cells, inhibit alloantigen recognition and processing of dendritic cells, and modulate B cell functions, including proliferation and antibody production to trigger im-munosuppression[16,17, 190-194]. Studies have shown that BMSCs could not only inhibit dendritic cell maturation, but also inhibit the antigen-presenting function by inhibiting their migration into lymph nodes, downregulating IL-12 expression, and upregulating IL-10 expression [195-197].BMSCs also inhibit the cytotoxic activity of NK cells by decreasing NKp30 and natural killer group 2 and downregulating member D, the receptors for natural killer cell activation, and target-cell killing [198].BMSCs also contribute to the transition of T cells from a proinflammatory state to an anti-inflammatory state and inhibit the formation of cytotoxic T lymphocytes [198, 199], which may partly explain the kidney protective function of BMSCs in autoimmune nephropathy. Compared with T cells, the influence of BMSCs on B cells is controversial. Some studies have shown that BMSCs can inhibit B cell proliferation, differentiation, and chemokine secretion, whereas other studies have shown that BMSCs could promote proliferation and stimulate the secretion of antibodies [198].
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