PART Ⅰ: Stem/progenitor Cell in Kidney: Characteristics, Homing, Coordination, And Maintenance
Mar 22, 2022
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PART Ⅰ: Stem/progenitor cell in the kidney: characteristics, homing, coordination, and maintenance
Jiewu Huang, Yaozhong Kong, Chao Xie, and Lili Zhou
Abstract
Renal failure has a high prevalence and is becoming a public health problem worldwide. However, renal replacement therapies such as dialysis are not yet satisfactory for their multiple complications. While stem/progenitor cell-mediated tissue repair and regenerative medicine show there is light at the end of the tunnel. Hence, a better understanding of the characteristics of stem/progenitor cells in kidneys and their homing capacity would greatly promote the development of stem cell research and therapy in the kidney field and open a new route to explore new strategies of kidney protection. In this review, we generally summarize the main stem/progenitor cells derived from kidneys in situ or originating from the circulation, especially bone marrow. We also elaborate on the kidney-specific microenvironment that allows stem/progenitor cell growth and chemotaxis and comment on their interaction. Finally, we highlight potential strategies for improving the therapeutic effects of stem/progenitor cell-based therapy. Our review provides important clues to better understand and control the growth of stem cells in kidneys and develop new therapeutic strategies.
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Introduction
Chronic renal disease (CKD) has become a public health problem, affecting over 10% of the global population. In high-risk populations, the prevalence of CKD is up to 50%[1]. Among the etiology of CKD, acute kidney injury(AKI), characterized by a rapid decline of renal function, is considered a key mediator of CKD and the subsequent end-stage of renal disease(ESRD)[2]. However, although renal replacement therapies such as dialysis could be a substitute for sustaining the basal renal function, the repair of the kidney itself is the main problem that needs to be solved. Although stem/progenitor cell-based tissue repair and regenerative medicine have been gradually investigated, there are still many areas unexplored. In this review, we summarize the general characteristics of stem/progenitor cells and their homing capacity in kidneys. We also highlight the microenvironments involved in stem/progenitor cell maintenance and provide potential strategies for improving stem/progenitor cell functions.
Stem/progenitor cells are a group of specific cells that possess the abilities of self-renewal, multipotent differentiation, and repair after organ injury [3]. Compared with stem cells, progenitor cells display a limited capability of differentiation. The microenvironment could greatly influence their differentiation and self-renewal [4]. Tissue-specific stem cells have been observed in many organs, including kidneys, bone marrow, gastrointestinal mucosa, liver, brain, prostate, and skin [4-8]. Stem/progenitor cells can differentiate into epithelial cells, myofibroblasts, and smooth muscle cells in embryonic metanephric mesenchyme [9-11]. The mesenchymal stem cell (MSC) population plays the important role in the embryogenesis of kidneys [12,13]. While in the adult kidney, the two different sources for stem/progenitor cells including resident renal stem/progenitor cells and circulating stem/progenitor cells which are mainly derived from bone marrow, also greatly facilitate the local repair processes through anti-inflammation and immune-modulatory effects [14-17]. There have been some studies showing that stem/progenitor cells could ameliorate kidney injury and improve renal function in ischemia/reperfusion injury (IRI)[3,5,15,18,19], nephrotic syndrome [20], acute renal failure by intramuscular injection of glycerol [21-23], and an adriamycin-induced model[24].
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Circulating stem/progenitor cells include endothelial progenitor cells (EPCs), hematopoietic stem cells (HSCs), and bone marrow-derived MSCs (BMSCs). EPCs, possessing the ability to repair endothelium, are derived from the bone marrow and can be mobilized to the peripheral circulation upon a variety of stimuli [25]. HSCs are a kind of stem cell in the bone marrow, owning the capacity to self-renew, proliferate, and differentiate to replenish the blood and immune systems [26]. HSC transplantation is effective in autoimmune disease [27-29], and also greatly improves renal function in auto-immune nephropathies such as IgA nephropathy [30,31], focal segmental glomerulosclerosis (FSGS)[32], and crescentic glomerulonephritis [33], by eradicating auto-reactive immune cells and regenerating a naive, self-tolerant immune system [34]. A large body of evidences indicate a great of potential therapeutic effects of BMSCs on AKI [35-37, CKD [37,38], FSGS [39,40],diabetic nephropathy [41-43], renovascular disease [44], lupus nephritis [45, 46], polycystic kidney disease [47], and others [48-51]. Studies have also shown that EPCs contribute to endothelial repair in IRI-induced kidneys [52,53] and restore the microvasculature, hemodynamics, and renal function in the stenotic kidney [54-56].To better understand the role of stem/progenitor cells in kidneys, we would focus on their characteristics and origin, the mechanism underlying their effects on kidney recovery, and strategies of stem/progenitor cell-based therapy in the following.
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Conclusions
There is a range of stem/progenitor cells, including kidney-resident stem/progenitor cells in the different areas of the kidney, with their own characteristics, and those that are derived from bone marrow and then home to the kidney. After kidney injury, these stem/progenitor cells can migrate into injured areas through a complicated mechanism, where they exert a protective effect on the inflammatory and hypoxic microenvironment of the injured kidney through differentiation or paracrine functions.
There are some appropriate and promising strategies for stem/progenitor cell-based therapies(Fig. 3). Stem cell preconditioning is an effective strategy to improve stem cell homing and survival, so as to enhance their kidney protective effect. However, the stem/progenitor cells function is impaired in CKD patients, leading to unsatisfactory therapeutic effects, but allogeneic stem/progenitor cells may be rejected. The application of bioactive molecules secreted by stem/progenitor cells could overcome this challenge. Because the combination with biomaterials can overcome the rapid clearance of stem/progenitor cells and their bioactive products in vivo, en-hance their renal selectivity, and provide a welcome microenvironment to promote their survival and function, this strategy should also be taken into consideration. Finally, with the potency to the biotechnological generation of a functional whole kidney in the future, a bioengineering method may be a promising future prospect.
Fig. 3 There are four potential strategies for improving the therapeutic effects of stem/progenitor cell-based therapy, including preconditioning, application of biomaterials, bioactive molecules, and bioengineering. Preconditioning mainly includes hypoxia, genetic modification, and administration with cytokines or chemical compounds. Biomaterials include hydrogels, biomaterial matrices, and other novel materials. The application of the bioactive molecules and EVs secreted by stem/progenitor cells is also helpful. And the application of dECM scaffold and ESCs or iPSCs to regenerate a functional whole organ is a prospective strategy in the future.
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