The origin of stem/progenitor cells in adult kidney
Mar 21, 2022
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PART Ⅱ: Stem/progenitor cell in the kidney: characteristics, homing, coordination, and maintenance
Jiewu Huang, Yaozhong Kong, Chao Xie, and Lili Zhou
CLICK HERE TO PART Ⅰ
Kidney-derived stem/progenitor cells
Many studies have demonstrated kidney-derived stem/progenitor cells in the adult kidney, the majority of which express MSC markers such as CD44, and kidney embryonic stem cell (ESC)markers such as CD24 and Pax-2, but not lineage-specific markers [5,9,22,24,57, 58], could self-renew and differentiate into mesodermal lineages, including adipogenic, osteogenic, and chondrogenic lineages. There are differences in stem/progenitor cells in different areas of the kidney(Fig. 1).
Renal stem/progenitor cells in glomeruli
Resident stem/progenitor cells with mesenchymal phenotypes have been found in mouse and human adult glomeruli [59, 60]. These cells can differentiate into mesodermal lineages, endothelial cells, podocytes, and mesangial cells under certain cultural conditions. Different from other kidney-derived stems/progenitor cells, they do not express CD133. These cells not only exhibit an MSC phenotype but also express ESC markers CD24 and Pax-2 [5, 9,57], which are negative in BMSCs. It has been found that CD24tCD133+-MSC-like cells in Bowman's capsule belong to renal stem/progenitor cells [21, 22], but CD133+ cells in glomeruli do not express CD24 and MSC markers and cannot undergo self-renew [59]. To identify the origin of these CD24tCD133-MSC-like cells, Bruno et al isolated them in glomeruli of an explanted kid-ney from a male donor transplanted into a female recipient and found that there was no double X chromosome in the 48-selected MSC-like cells. Hence, they believed that these cells were kidney-resident MSCs rather than BMSCs homing to the kidney. Another article shows that although resident kidney MSCs from glomeruli can differentiate into mesodermal lineages, they are different from BMSCs. Compared with BMSCs, resident kidney MSCs exhibit mineralized nodules rather than mineralization of the whole monolayer after differentiating into osteogenic lineages. Besides, the adipogenic differentiation in kidney-resident MSCs seems to be less efficient [60]and also indirectly identified that these stem cells are not derived from bone marrow.
Renal stem/progenitor cells in Bowman's capsule
Many studies have confirmed the existence of CD24tCD133t cells in Bowman's capsule, especially in the urinary pole of Bowman's capsule. Compared with all other parenchymal cells of the kidney, they show higher resistance to injurious agents [20, 21,61-63]. We can distinguish their source because renal stem/progenitor cells in Bowman's capsule express CD106, but stem/progenitor cells in the tubules do not. Besides, CD133tCD24tCD106t cells exhibit a higher rate of proliferation than those with negative expression of CD106. These cells with CD133*CD24tCD106t expression prefer to differentiate toward the phenotypes of podocyte lineage. tubular li and that contrast, By .] CD133*CD24tCD106-cells mainly prefer to tubular lineage differentiation [21]. CD133*CD24'CD106* cells are primarily located in the urinary pole of Bowman's capsule, while CD133*CD24'CD106～cells are mostly expressed in proximal tubules, so they are close to each other. The abilities of self-renewal and differentiation of CD133tCD24tCD106-cells are less than CD106* cells. However, they both express vimentin, cytokeratin 7, and cytokeratin 19, highlighting the similarity between the two cells [64]. CD133'CD24+CD106- cells may derive from CD133tCD24'CD106* cells and this represents a more committed step toward complete differentiation into the tubular lineage [21].
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Renal stem/progenitor cells in Bowman's capsule are a special type of parietal epithelial cells, which exhibit a high potential of self-renewal and multilineage differentiation and express kidney ESC as well as MSC marker CD44, but not lineage-specific markers [20, 22, 65]. These cells also express the stem cell-specific transcription factors Oct-4 and Bmi-1[22].Oct-4 is normally expressed in ESCs, for maintaining their immature state, and is required for the pluripotency of germ cells [66]. Bmi-1 is a critical factor in the maintenance of the self-renewal ability of adult stem/progenitor cells. Knockout of Bmi-1 in renal stem/progenitor cells would result in their apoptosis and decrease in their capacity of self-renewal [67]. Notably, the abilities of self-renewal and differentiation are different considering the location. Those cells closer to the urinary pole of Bowman's capsule have more abilities of differentiation and proliferation than those closer to the vascular pole [20]. Because renal stem/progenitor cells in Bowman's capsule express kidney ESC markers, thus they are also believed as residual kidney stem/progenitor cells rather than BMSCs.
Fig.1 Multiple stem/progenitor cells in the kidney, which are located in the kidney in situ or originated from circulation, especially bone marrow. Furthermore, there are differences in these kidney-derived stem/progenitor cells considering their location. Stem/progenitor cells in glomeruli are CD24+CD133-MSC-like cells. The CD133+CD24*CD106+-stem/progenitor cells are primarily located in the urinary pole in Bowman's capsule. Those cells closer to the urinary pole have more activities than those closer to the vascular pole. CD133CD24+CD1067 cells are in tubules, especially proximal tubules, with fewer mitochondria and less cytoplasm and without brush border than other tubular epithelial cells. In addition, CD90+Pax-2tCD133--MSC-like cells, Pax-2+ tubule-like cells,and Pax-8+ cells also locate in tubules. Notably, Sox9Lgr4CD133+Pax-27 cells, primarily located in proximal tubules with epithelial polarity and brush border, could differentiate into proximal tubule, a loop of Henle, and distal tubule segments, but not into collecting duct. In the S3 segment of the nephron, there is a group of Pax-2* stem/progenitor cells, which have the perfect repair capabilities although they have an immature tubular epithelial-like phenotype. The renal papilla is also a niche for renal stem/progenitor cell homing. These CD24CD133+ spindle-shaped cells are primarily located in the very outer part of the papilla which is in close proximity to tubules. Besides, there are also pericytes and CD133+-kidney-resident MSCs close to the vessel in the interstitium
Renal stem/progenitor cells in tubules and interstitium in the cortex
There are stem/progenitor cells in tubules, especially proximal tubules [5, 11, 21, 24,64,68]. Most of them are capable to differentiate into tubular epithelial cells and even could differentiate into mesodermal lineages such as adipogenic, osteogenic, and chondrogenic lineages. But it still has differences. A study shows that these cells express renal ESC markers such as Pax-2 and have a spindle-shaped morphology. These cells have a positive expression of CD90 and CD44 but are CD133-negative [5]. Other studies show that stem/progenitor cells in tubules are Pax-2 as well as some MSC marker-positive, although there is no morphologic difference between them and other tubular cells [11]. A study also shows that they express MSC markers of CD44 and renal stem/progenitor cell marker Pax-8. They have a strong ability of self-renewal and differentiation into tubule epithelial cells. Interestingly, they could also be induced to differentiate into mesodermal lineages in vitro as well [24].
Most studies have shown that there are CD24'CD133*- stem/progenitor cells in the tubules, which can regenerate tubular cells and improve renal function after kidney injury [21,63,64,69]. They own the capacities of self-renewal and differentiation into tubular cells [21]. Although they are Pax-2 and CD44 negative, they could express vimentin, cytokeratin 7, and cytokeratin 19, none of which are expressed in the differentiated proximal epithelial cells [63, 64]. What is more, compared with tubular epithelial cells, they have fewer mitochondria and less cytoplasm and have no brush border. Some researchers think that there is also a possibility that this phenotype is the result of the loss of the brush border because of the dedifferentiation of these cells toward a more mesenchymal phenotype. As a result, these cells could be commonly mistaken as renal stem/progenitor cells in tubules [63,69].
It has been found that Sox9* cells are in adult kidneys, which own the high capacity of proliferation and mesodermal lineage differentiation [70]. These stem/progenitor cells are primarily located in proximal tubules, and they have epithelial polarity and brush border [68]. These cells express CD133 and Lgr4, the markers of progenitor cells, but have a negative expression of Pax-2 or common MSC markers. They could differentiate into proximal tubules, a loop of Henle, and distal tubule segments, but not into collecting ducts. Sox9t cells are found in the early stage of kidney development and disappear quickly after birth. They possess the high ability of proliferation and are the predominant contributor to repair in tubules after kidney injury. Because most of the epithelial cells except those in collecting ducts and glomeruli are descendants of Sox9t cells in the kidney, the studies have different arguments about the increase in Sox9+ cells after kidney injury. They think that although most descendants of Sox9t cells no longer express the Sox9 gene in normal kidneys, it is activated after kidney injury. The researchers think that de novo activation of Sox9 rather than the expansion of the resident Sox9t population contributes more to the recovery of kidneys [68, 70, 71].
Pax-2t cells have been found in the S3 segment of the nephron, characterized by an immature phenotype of tubular epithelial cells and the expression of progenitor and mesenchymal cell markers. These cells have the abilities of self-renewal, differentiation, and tissue repair. They can reconstitute three-dimensional nephron-like structures, including glomeruli, proximal tubules, the loop of Henle, distal tubules, and collecting ducts, but not vasculature. They could also migrate into injured areas and differentiate into mature tubular epithelial cells in vivo [3, 72, 73].
CD133* cells with MSC and kidney ESC markers are located in the interstitium in the adult kidney cortex. These cells could differentiate into epithelial or endothelial cells and grow into tubular structures or functional vessels, but they have limited ability of self-renewal [10]. Because they do not express the hematopoietic markers CD34 and CD45, they might be of kidney origin. However, it has also been proposed that these cells may originate from a bone marrow-derived population, which has homed to the kidney a long time ago. Hence, they have lost their markers of hematopoietic lineage.
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Renal stem/progenitor cells in papilla and interstitium of the medulla
The renal papilla is a niche for adult renal stem/progenitor cells[15,18,74-76]. These CD24*CD133* spindle-shaped cells co-express MSC markers such as stem cell antigen-1 (Sca-1) and epithelial proteins, have a high activity of telomerase, and can differentiate into mesodermal lineages and endothelial cells [15,18]. These cells are mainly located in the very outer part of the papilla, in close proximity to the tubules, and some are adjacent to the tubular basal surface. These cells can also be found in the cortex and medulla to a less extent [15]. After the kid-ney injury, they proliferate and migrate into the injured areas to repair tubules, although their generative capacity is restricted.
Lee et al. also found that there are some spindle-shaped cells with kidney ESC markers in the interstitium of the medulla. These cells could differentiate into endothelial, osteoblastic, and tubular epithelial lineages in vitro. Moreover, they are able to differentiate into endothelial cells and tubular cells and preserve renal function after ischemic renal injury [19].
Remaining embryonic kidney stem/progenitor cells
Renal progenitor cells in human embryonic kidney ex-press CD24 and CD133 and have the capacities of self-renewal and multi-lineage differentiation. Like most renal stem/progenitor cells, these cells express MSC and kidney ESC markers, but not hematopoietic markers such as CD45. They construct the human primordial nephron in the early stage, but disappear progressively during nephron development, while the remnant kidney ESCs which locate primarily in the urinary pole of Bowman's capsule represents <2% of whole cells in the adult kidney [23]. However, these cells can differentiate into many kinds of kidney-resident cells and even into mesodermal lineages. After AKI, renal progenitor cell administration could enhance tissue repair and induce the recovery of renal function as well as structure. Because most renal stem/progenitor cells exhibit a similar phenotype to embryonic kidney stem/progenitor cells, renal CD24tCD133 stem/progenitor cells in the adult kidney may all be derived from renal ESCs [23].
Renal stem/progenitor cells and kidney-resident MSCs
Resident MSCs have also been isolated from adult kidneys. Their characteristics are similar to those of ESCs. These cells are able to differentiate into a wide variety of lineages, including mesodermal lineages, endothelial cells, and erythropoietin-producing fibroblasts. After kidney injury, they migrate into the kidney and promote the recovery of renal function [77-79]. Some researchers believe that the MSC-like renal stem/progenitor cells in embryonic and adult kidneys are merely resident MSCs in the kidney, including in glomeruli, tubules, interstitium, and papilla [13]. Besides, it has been proposed that kidney-resident MSCs are derived from perivascular cells [60], which would explain why renal stem/progenitor cells can be isolated from many parts of the kidney and their MSC-like appearance.
Pericytes, which are vascular mural cells with a function of angiogenesis in the kidney [80], modulate the endothelial phenotype and the extracellular matrix composition to stabilize vessels. Mesangial cells are described as glomerulus-specific pericytes [81]. Of note, some markers of pericytes such as CD146 and CD73 are also expressed in MSCs[13]. Hence, pericytes, exhibiting the potential of mesodermal lineage differentiation, are thought to be renal stem/progenitor cells and considered as resident MSCs around capillary walls [13, 82-84].
Some Gli1+ cells around the vasculature expressing the typical MSC markers are considered immature pericytes. They possess mesodermal differentiation capability in the kidney and contribute greatly to kidney fibrosis. It has been revealed that around 45% of myofibroblasts in the kidney are derived from these Glil* MSC-like cells[80]. Another study has also shown that pericytes are the main source of myofibroblasts in the kidney[85]. These suggest stem/progenitor cells may also have bad side effects besides repair.
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Circulating bone marrow-derived stem/progenitor cells homing to the adult kidney
Bone marrow-derived stem/progenitor cells(BMDCs)can be released from the bone marrow into the peripheral blood and then move into the injured area to improve the renal function after being attracted by a variety of growth factors and inflammatory cytokines released from the injured area [53,86-90]. It has been reported that in male patients who have received a kidney transplant from a female donor, there are some BMDCs with a Y chromosome in the kidney with the expression of a tubular epithelial cell or podocyte phenotype. This demonstrates that circulating BMDCs can home to the kidney and differentiate into tubular epithelial cells and podocytes [91]. Imasawa et al. also found that after tail vein injection of enhanced green fluorescent protein (EGFP)-labeled BMDCs and subsequent sufficient perfusion with PBS to remove circulating EGFP+ cells in glomeruli, the remaining EGFP+ cells exhibit several characteristics and markers of glomerular mesangial cells. The numbers of which increase in a time-dependent manner, suggesting BMDCs own the ability to migrate into the kidney and transdifferentiate into mesangial cells after kidney injury [92].
It is reported that BMDCs can fuse with somatic cells [93, 94], which can also lead to the presence of BMDC markers and somatic cell markers in the same cells. However, these studies cannot elucidate whether the endothelial cells, tubular epithelial cells, podocytes, and glomerular mesangial cells detected in this study arise from transdifferentiation or cell fusion [91, 92, 95-99]. In order to answer this question, a study performed the transplantation of bone marrow from female mice into male Fah-/- mice. The presence of the host marker Y chromosome in Fah* tubules, the donor marker, would indicate cell fusion. The study shows that at least half of the bone marrow-derived tubular epithelial cells are generated by cell fusion. However, Fah+ Y- tubular epithelial cells may also be generated by cell fusion, rather than from direct transdifferentiation of BMDCs, because it may be the result of decreased division, loss of the Y chromosome, or the artificial limitations of tissue section analysis [100].
After administration of male mouse HSCs into female ischemic mice, there are some cells exhibiting a renal proximal tubular cell phenotype and carrying a Y chromosome, indicating that HSCs could be recruited and transdifferentiated into tubular epithelial cells [87, 101,102]. Another study shows that HSCs can also transdifferentiate into glomerular mesangial cells [103]. Because the frequency of cell fusion is rare per 10°bone marrow cells and the number of HSC-derived cells greatly exceeds the frequency of cell fusion, the researchers believe that HSCs are unlikely to be involved in the cell fusion, although it cannot be completely excluded [87]. Ikarashi et al. found that after administration of EGFP+-bone marrow cells in a progressive glomerulosclerosis rat model, some glomerular endothelial cells express the endothelial cell markers PECAM-1 or RECA-1 with the colocalization of EGFP, suggesting the involvement of EPCs in glomerular endothelial cell turnover [104]. Other studies also show that EPCs in the injured kidney could differentiate into endothelial cells and contribute to the rebuilding of glomerular capillaries [89, 105-107]. Researchers believe that EPC-derived cells are prone to transdifferentiate rather than cell fusion because cell fusion is a very low-frequency event. The numbers of EPC-derived cells greatly exceed the frequency of cell fusion. Furthermore, cell fusion would result in the loss of cell function and lower expression of EGFP, which is contradictory with its significant therapeutic effects[104]. Ezquerra et al. found that after tail vein injection of EGFP+-BMSCs, they exert a renoprotective effect on diabetic nephropathy mice. EGFP+-BMSCs are found in the kidney of diabetic mice while they are undetectable in normal mice, suggesting that the injured kidney could recruit BMSCs [41]. Another study shows that after transplanting the bone marrow of EGFP-positive rats into wild-type rats, BMSC transdifferentiates into mesangial cells to provide structural support for glomerular capillaries [108]. Other studies also show that BMSCs are able to transdifferentiate into podocytes, mesangial cells, tubular epithelial cells, etc. both in vitro or vivo [88,109-111]. Although cell fusion is a low-frequency event and it is contradictory with the significant therapeutic effects, it cannot be completely excluded considering it as a repair mode.
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