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The Continuing Story of Renal Repair with Stem Cells

October 2007
Journal of the American Society of Nephrology 18(9):2423-4

October 2007
18(9):2423-4

DOI:10.1681/ASN.2007070769

Source
PubMed

Authors:

Enyu Imai

Nakayamadera Imai Clinic

Content uploaded by Enyu Imai

Content may be subject to copyright.

The Continuing Story of Renal

Repair with Stem Cells

Enyu Imai* and Hirotsugu Iwatani

†

*Department of Nephrology, Osaka University Graduate School of

Medicine, Suita, and

†

Department of Medicine, Osaka Koseinen-

kin Hospital, Osaka, Japan

J Am Soc Nephrol 18: 2423–2428, 2007.

doi: 10.1681/ASN.2007070769

Renal stem cells are still a hot topic, but their location and

mechanism of action continue to elude. The therapeutic po-

tential of intrinsic stem cells to the recovery of damaged kid-

ney has been suggested by a number of recent experiments,

whereas the role of various other kinds of administered stem

cells is still controversial. There are two large questions to

address regarding the role of stem cells in kidney repair. The

first is whether the restoration of nephrons requires either

intrinsic renal progenitor cells, bone marrow– derived stem

cells, or both. The second pertains to the role of stem cells in

the repair process itself, specifically whether stem cells replace

damaged tubular cells by transdifferentiation or accelerate

repair by an indirect mechanism.

In the early 2000s, pluripotent bone marrow– derived

stem cells were thought to contribute directly to regeneration

of the kidney.

1,2

Bone marrow contains at least three stem cell

lineages: Hematopoietic stem cells (HSC), mesenchymal

stem/stromal cells (BMSC), and endothelial progenitor cells.

Crude preparations of bone marrow– derived stem cells seem

to have a high capacity for transdifferentiation and therefore

are able to replace damaged renal tissue with tubular epithe-

lial cells, mesangial cells, endothelial cells, and even podo-

cytes. In these studies, double staining of green fluorescence

protein or Y chromosomes from bone marrow– derived stem

cells in addition to kidney cell–specific surface markers pro-

vided evidence of transdifferentiation and repair, although

the issue of cell fusion looms large and is still controversial.

In other studies, the injection of BMSC protects the kid-

ney from toxin or ischemia/reperfusion injury and attenuates

lost renal function, whereas injected HSC do not have the

same effect.

In both approaches, however, bone marrow–

derived stem cells seemed to contribute relatively small num-

bers of cells (3 to 22%) to regenerating renal tubular

and

glomerular cell populations

; that is, the majority of repara-

tive cells were derived from intrinsic kidney cells. In studies

from this period, the notion of transdifferentiation was used

with loosely defined meaning. The definition of transdiffer-

entiation in the stem cell field is the complete conversion of a

cell from one lineage to another lineage with clearly altered

tissue-specific markers and functions. However, the com-

pleteness of this definition has not been demonstrated in

many studies.

If recent studies argue against the direct differentiation of

most bone marrow– derived stem cells into kidney cells, then

some other mechanism must contribute to kidney repair.

Duffield et al.,

for example, reported that adoptively trans-

ferred BMSC are not detected in the kidney, lung, or spleen,

whereas injection of BMSC ameliorated repair of the kidney

in the ischemia/reperfusion model. Togel et al.

also demon-

strated that administration of BMSC significantly improved

renal function in the ischemia/reperfusion model, but none

of the cells differentiated into tubular or endothelial cells.

In this issue of JASN,Biet al.

provide another mecha-

nism. They demonstrate that adoptive transfer of BMSC into

the peritoneal cavity or passive transfer of condition medium

from cultured BMSC accelerates recovery from cisplatin-in-

duced acute renal failure in mice. This is new evidence that

humoral factors from BMSC—and not BMSC per se—are

necessary for recovery from acute kidney injury. Further-

more, injected BMSC localize in the vasculature of the lung

but not in the kidney at all. These results suggest that the local

presence of BMSC in the kidney is not necessary for repair

and that the humoral factors secreted by BMSC at remote

locations are sufficient to protect or repair injured nephrons.

Although many of us assume that tissue regeneration after

acute kidney injury may subtly orchestrate the temporal and

spatial expression of various growth factors or cytokines as in

the developmental stage, it is of great interest that systemic

administration of condition medium from BMSC affords

this renoprotective effect as well, presumably activating in-

trinsic stem cells in the kidney through endocrine or para-

crine action. What these intrinsic renal cells are and what in

the conditioned medium are the critical mediators of this

signaling are not yet clear.

The candidate factors are plentiful. We know from other

experiments that the therapeutic effects of angiogenic growth

factors such as vascular endothelial growth factor (VEGF)

and hepatocyte growth factor (HGF)

have been reported in

tissue injury followed by fibrosis. VEGF and HGF are se-

creted by BMSC, and administration of VEGF or HGF im-

proves hemodynamics, increases capillary density, acceler-

ates tissue repair, and inhibits fibrosis in injured tissues.

BMSC also seem to have immunomodulatory properties and

inhibit alloantigen-induced differentiation, maturation, and

Published online ahead of print. Publication date available at www.jasn.org.

Correspondence: Dr. Enyu Imai, Department of Nephrology, Osaka Univer-

sity Graduate School of Medicine, 2–2 Yamadaoka, Suita 565-0871, Japan.

Phone: ⫹81-6-6879-3632; Fax: ⫹81-6-6879-3639; E-mail imai@medone.med.

osaka-u.ac.jp

UP FRONT MATTERS

EDITORIALS www.jasn.org

J Am Soc Nephrol 18: 2423–2428, 2007 ISSN : 1046-6673/1809-2423 2423

activation of dendritic cells. They also decrease IL-2 produc-

tion and IL-2 receptor expression in activated T cells; induce

regulatory T cells; and suppress the activation, proliferation,

chemotaxis, and antibody production of B cells.

These immu-

nosuppressive actions of BMSC are not fully understood; how-

ever, some speculate that secreted, soluble factors suppress in-

flammation and mediate the beneficial actions in tissue repair.

What are the cellular targets of this conditioned medium?

Presumably they are renal stem cells or progenitor cells. Kid-

ney stem cells have been described in the renal papilla,

10,11

Bowman’s capsule,

and the S3 segment of the proximal tu-

bule.

13–15

CD133

⫹

/CD24

⫹

stem cells in or near Bowman’s

capsule can differentiate into epithelial and endothelial cells.

Oct4-, Pax-2–, and CD90-expressing cells in the proximal tu-

bules differentiate into tubular cells.

Multipotent renal pro-

genitor cells expressing Pax-2, Sca-1, and Musashi-1 have been

isolated from microdissected S3 segments.

Taking advantage

of the slow cycling of stem cells, a population of proximal tu-

bular epithelial cells have also been isolated in important ex-

periments.

Further studies, of course are necessary to identify the ben-

eficial effects of soluble factors in the condition medium of

BMSC on kidney repair, and confirmatory experiments are

needed in other models of acute kidney injury and experimen-

tal glomerulonephritis. For the future, more vertical research

on mechanisms of kidney regeneration is needed, and a high

priority should be placed on the identification of the therapeu-

tic factors and target cells in and around the nephron.

DISCLOSURES

None.

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Anti–Endothelial Cell

Antibodies in Vasculitis

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J Am Soc Nephrol 18: 2425–2426, 2007.

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Anti– endothelial cell antibodies have been described in asso-

ciation with small vessel systemic vasculitides since the late

1980s. Opinions have waxed and waned about their impor-

tance. An early study from this group suggested they were

present in 59% of 168 samples from patients with Wegener’s

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while a contem-

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EDITORIALS www.jasn.org

2424 Journal of the American Society of Nephrology J Am Soc Nephrol 18: , 2007

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In order to establish whether extra-renal cells contribute to the turnover and repair of renal tissues, this study examined kidneys of female mice that had received a male bone marrow transplant and kidney biopsies from male patients who had received kidney transplants from female donors. By using in situ hybridization to detect Y-chromosomes it could be demonstrated that circulating stem cells frequently engraft into the kidney and differentiate into renal parenchymal cells. In the human renal grafts it was confirmed that some of the recipient-derived cells within the kidney exhibited a tubular epithelial phenotype, by combining in situ hybridization with immunostaining for the epithelial markers CAM 5.2 and the lectin Ulex europaeus. Female mouse recipients of male bone marrow grafts showed co-localization of Y-chromosomes and tubular epithelial markers Ricinus communis and Lens culinaris, and a specific cytochrome P450 enzyme (CYP1A2) indicating an appropriate functional capability of clustered newly formed marrow-derived tubular epithelial cells. Y-chromosome-containing cells were observed within glomeruli, with morphology and location appropriate for podocytes. Within the murine kidney, these Y-chromosome-positive cells were negative for the mouse macrophage marker F4/80 antigen and leukocyte common antigen, but were vimentin-positive. The presence of bone marrow-derived cells was noted in both histologically normal mouse kidneys and in human transplanted kidneys suffering damage from a variety of causes. These data indicate that bone marrow cells contribute to both normal turnover of renal epithelia and regeneration after damage, and it is suggested that this could be exploited therapeutically.

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The present study was conducted to explore renal progenitor-like cells that are actively engaged in tubular regeneration after injury. For addressing this issue, the existence of label-retaining cells (LRC; slow-cycling cells) in normal rat kidneys by in vivo bromodeoxyuridine (BrdU) labeling was examined. LRC were scattering among renal epithelial tubular cells of normal rat kidneys. During the recovery after renal ischemia, LRC underwent cell division and most of them became positive for proliferating cell nuclear antigen. In contrast, proliferating cell nuclear antigen-positive but BrdU-negative tubular cells were rarely observed, suggesting that cells proliferating during tubular regeneration are essentially derived from LRC. At an early phase of tubular regeneration, descendants of LRC expressed a mesenchymal marker, vimentin, and eventually became positive for an epithelial marker, E-cadherin, after multiple cell divisions. These findings suggested that LRC function as a source of regenerating cells to replace injured cells. Collectively, it was concluded that LRC are renal progenitor-like tubular cells that provide regenerating cells, which actively proliferate and eventually differentiate into epithelial cell, during tubular regeneration. It may be possible to regenerate renal tubules in vivo through the activation of LRC.

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Injury to a target organ can be sensed by bone marrow stem cells that migrate to the site of damage, undergo differentiation, and promote structural and functional repair. This remarkable stem cell capacity prompted an investigation of the potential of mesenchymal and hematopoietic stem cells to cure acute renal failure. The model of renal injury induced in mice by the anticancer agent cisplatin was chosen. Injection of mesenchymal stem cells of male bone marrow origin remarkably protected cisplatin-treated syngeneic female mice from renal function impairment and severe tubular injury. Y chromosome-containing cells localized in the context of the tubular epithelial lining and displayed binding sites for Lens culinaris lectin, indicating that mesenchymal stem cells engraft the damaged kidney and differentiate into tubular epithelial cells, thereby restoring renal structure and function. Mesenchymal stem cells markedly accelerated tubular proliferation in response to cisplatin-induced damage, as revealed by higher numbers of Ki-67-positive cells within the tubuli with respect to cisplatin-treated mice that were given saline. Hematopoietic stem cells failed to exert beneficial effects. These results offer a strong case for exploring the possibility that mesenchymal stem cells by virtue of their renotropic property and tubular regenerative potential may have a role in the treatment of acute renal failure in humans.

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Article

Nov 2004

Vascular endothelial growth factor (VEGF) is essential for maintenance of the glomerular capillary network. The present study investigated the effects of VEGF in rats with progressive crescentic glomerulonephritis (GN). Necrotizing and crescentic GN was induced in rats by injection of anti-rat glomerular basement membrane (GBM) antibody. The alterations of glomerular capillaries and glomerular VEGF expression were assessed. In addition, the effects of continuous VEGF165 administration (10 microg/100 g per d) on glomerular capillaries, glomerular inflammation, and the course of crescentic GN were examined. The appropriate timing of VEGF administration in progressive GN also was evaluated. In anti-GBM GN, necrotizing and crescentic glomerular lesions occurred by day 7, and newly formed necrotizing lesions reoccurred by week 3. Expression of VEGF was markedly reduced in necrotizing and crescentic lesions. Capillary repair was impaired after capillary destruction in necrotizing and crescentic glomeruli, which rapidly progressed to sclerotic glomeruli with chronic renal failure. In contrast, in the rats that received VEGF165 administration from day 7, the necrotizing and crescentic lesions recovered and renal function significantly improved in week 4. This was evident by proliferating endothelial cells and glomerular capillary repair. In addition, VEGF administration decreased intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 expression in glomeruli (particularly on endothelial cells), reduced glomerular infiltrating CD8-postive and ED-1-positive cells, and inhibited the newly formed necrotizing lesions. VEGF administration was apparently effective against both the inflammatory and necrotizing glomerular lesions. These results suggest that VEGF administration resolves glomerular inflammation and accelerates glomerular recovery in the progressive necrotizing and crescentic GN. The therapeutic application of VEGF may be clinically useful for severe GN accompanied by extensive glomerular inflammation and endothelial injury.

T??gel, F, Hu, Z, Weiss, K, Isaac, J, Lange, C and Westenfelder, C. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol 289: F31-F42

Article

Aug 2005

Severe acute renal failure (ARF) remains a common, largely treatment-resistant clinical problem with disturbingly high mortality rates. Therefore, we tested whether administration of multipotent mesenchymal stem cells (MSC) to anesthetized rats with ischemia-reperfusion-induced ARF (40-min bilateral renal pedicle clamping) could improve the outcome through amelioration of inflammatory, vascular, and apoptotic/necrotic manifestations of ischemic kidney injury. Accordingly, intracarotid administration of MSC (approximately 10(6)/animal) either immediately or 24 h after renal ischemia resulted in significantly improved renal function, higher proliferative and lower apoptotic indexes, as well as lower renal injury and unchanged leukocyte infiltration scores. Such renoprotection was not obtained with syngeneic fibroblasts. Using in vivo two-photon laser confocal microscopy, fluorescence-labeled MSC were detected early after injection in glomeruli, and low numbers attached at microvasculature sites. However, within 3 days of administration, none of the administered MSC had differentiated into a tubular or endothelial cell phenotype. At 24 h after injury, expression of proinflammatory cytokines IL-1beta, TNF-alpha, IFN-gamma, and inducible nitric oxide synthase was significantly reduced and that of anti-inflammatory IL-10 and bFGF, TGF-alpha, and Bcl-2 was highly upregulated in treated kidneys. We conclude that the early, highly significant renoprotection obtained with MSC is of considerable therapeutic promise for the cell-based management of clinical ARF. The beneficial effects of MSC are primarily mediated via complex paracrine actions and not by their differentiation into target cells, which, as such, appears to be a more protracted response that may become important in late-stage organ repair.

Restoration of tubular epithelial cells during repair of the postischemic kidney occurs independently of bone marrow-derived stem cells

Article

Aug 2005

Ischemia causes kidney tubular cell damage and abnormal renal function. The kidney is capable of morphological restoration of tubules and recovery of function. Recently, it has been suggested that cells repopulating the ischemically injured tubule derive from bone marrow stem cells. We studied kidney repair in chimeric mice expressing GFP or bacterial beta-gal or harboring the male Y chromosome exclusively in bone marrow-derived cells. In GFP chimeras, some interstitial cells but not tubular cells expressed GFP after ischemic injury. More than 99% of those GFP interstitial cells were leukocytes. In female mice with male bone marrow, occasional tubular cells (0.06%) appeared to be positive for the Y chromosome, but deconvolution microscopy revealed these to be artifactual. In beta-gal chimeras, some tubular cells also appeared to express beta-gal as assessed by X-gal staining, but following suppression of endogenous (mammalian) beta-gal, no tubular cells could be found that stained with X-gal after ischemic injury. Whereas there was an absence of bone marrow-derived tubular cells, many tubular cells expressed proliferating cell nuclear antigen, which is reflective of a high proliferative rate of endogenous surviving tubular cells. Upon i.v. injection of bone marrow mesenchymal stromal cells, postischemic functional renal impairment was reduced, but there was no evidence of differentiation of these cells into tubular cells of the kidney. Thus, our data indicate that bone marrow-derived cells do not make a significant contribution to the restoration of epithelial integrity after an ischemic insult. It is likely that intrinsic tubular cell proliferation accounts for functionally significant replenishment of the tubular epithelium after ischemia.

The Continuing Story of Renal Repair with Stem Cells

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