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The Regenerative Potential of the Kidney: What Can We

Learn from Developmental Biology?

Franca Anglani &Federica Mezzabotta &Monica Ceol &

Rosalba Cristofaro &Dorella Del Prete &

Angela DAngelo

Published online: 17 August 2010# Springer Science+Business Media, LLC 2010

Abstract Cell turnover in the healthy adult kidney is very

slow but the kidney has a strong capacity for regenerationafter acute injury. Although many molecular aspects of this

process have been clarified, the source of the newly-formed

renal epithelial cells is still being debated. Several studies

have shown, moreover, that the repair of injured renal

epithelium starts from mature tubular cells, which enter into

an activated proliferative state characterized by the reappear-

ance of mesenchymal markers detectable during nephro-

genesis, thus pointing to a marked plasticity of renal epithelial

cells. The regenerative potential of mature epithelial cells

might stem from their almost unique morphogenetic process.

Unlike other tubular organs, all epithelial and mesenchymal

cells in the kidney derive from the same germ layer, the

mesoderm. In a fascinating view of vertebrate embryogenesis,

the mesoderm might be seen as a cell layer capable of

oscillating between epithelial and mesenchymal states, thus

acquiring a remarkable plasticity that lends it an extended

potential for innovation and a better control of three-

dimensional body organization. The renal papilla contains a

population of cells with the characteristic of adult stem cells.

Mesenchymal stromal stem cells (MSC) have been found to

reside in the connective tissue of most organs, including thekidney. Recent studies indicate that the MSC compartment

extends throughout the body postnatally as a result of its

perivascular location. Developmental biology suggests that

this might be particularly true of the kidney and that the

papilla might represent the perivascular renal stem cell niche.

The perivascular niche hypothesis fits well with the evolving

concept of the stem cell niche as an entity of action. It is its

dynamic capability that makes the niche concept so important

and essential to the feasibility of regenerative medicine.

Keywords Renal adult stem cells . Kidney development.

EMT . Cell plasticity . Pericytes . Perivascular niche

Introduction

The adult mammalian renal tubular epithelium exists in a

relatively quiescent to slowly replicating state, and cell turnover

in the healthy adult kidney is very slow. The kidney has a strong

capacity for regeneration, despite the postnatal mammalian

kidney being unable to generate new nephrons in response to

nephron loss. No new nephrons are generated after 36 weeks of

gestation in humans, but a renal stem cell system is supposed to

contribute to the replacement of postnatal cell types [1].

The anatomical and functional recovery of renal integrity

after injury is accompanied by the activation of sophisti-

cated processes that have yet to be fully understood, by

means of which damaged tubular cells are replaced by

normal, well-functioning cells that reorganize their archi-

tecture to recreate a normal tubule. Although many of the

molecular details of this process have been clarified over

the last 20 years, the cellular source of the newly-formed

renal epithelial cells is still being debated. Some studies

F. Anglani :F. Mezzabotta :M. Ceol : R. Cristofaro

Laboratory of Kidney Histomorphology and Molecular Biology,

Department of Medical and Surgical Sciences, University of Padua,

Padua, Italy

D. Del Prete :A. DAngelo

Division of Nephrology, Department of Medical and Surgical

Sciences, University of Padua,

Padua, Italy

F. Anglani (*)

Divisione di Nefrologia, Policlinico IV piano,

Laboratorio di Istomorfologia e Biologia Molecolare del Rene,

Via Giustiniani n2,

35128 Padova, Italy

e-mail: franca.anglani@unipd.it

Stem Cell Rev and Rep (2010) 6:650657

DOI 10.1007/s12015-010-9186-6

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showed that novel cells derive from the division of

differentiated cells [2, 3]; others claimed that subpopula-

tions of renal tubular cells act as progenitor cells [ 47]; and

yet others demonstrated that hematopoietic stem cells and

circulating mesenchymal stem cells can repopulate the

tubular cell system [8, 9]. Indeed, a wide variety of

potential progenitor or adult stem cell populations have

been identified in human and rodent kidneys on the basis oftheir functional and/or phenotypic characteristics in the

glomerular and in the tubular/interstitial compartments

(reviewed in [10]) (Fig.1). Many organs, particularly those

with a high cell turnover, are believed to harbor a stem cell

population that sustains normal organ structure and con-

tributes to repair, and some of these organs contain several

types of stem/precursor cells that provide new cells for

specific locations and functions. Recent studies have shown

in organs such as the skin [21] and liver [22] that the

precursor cells responsible for homeostatic cell turnover

differ from those responsible for cell replacement after

injury. Given the complexity of the renal architecture andthe numerous cell types involved, the kidney probably has

multiple mechanisms of cell renewal and regeneration too.

Cell renewal and regeneration

Most data on the origin of new tubular epithelial cells in the

kidney derive from studies on the regeneration/repair

process after tubular necrosis due to ischemic injury. Since

the S3 segment of the proximal tubule is the part of the

nephron most susceptible to injury and appears to have the

highest proliferation rate (in young rats at least), most

studies on regenerative nephrogenesis have focused on the

proximal tubular epithelial cells (TECs). Vogetseder et al.

[2325] showed that cell proliferation in the healthy kidney

of young rats relies on differentiated TEC division. Moreimportantly, in a recent study using a refined technique

called genetic fate mapping, Humphereys et al. [26] clearly

demonstrated that differentiated TECs surviving after

ischemia-reperfusion injury generated most, if not all, new

tubular epithelial cells.

Taking a morphological approach, Vogetseder et al. [23]

showed that, in the healthy kidney, the slow cycling cells in

the S3 segments (label retaining cells, LRCs)identifiable

from their ability to retain BrdUexpressed markers of

terminal differentiation and a typical tubular cell polarity.

This study showed that the cell proliferation pattern in the

S3 segment fails to display the characteristic features of astem cell system. The authors also found that the

proliferative capacity of renal TECs comes from a large

reserve of cells in the G1 phase, which ensures a rapid

proliferative response when needed. This was a theory first

advanced by Lin et al. [27] who tagged renal TECs with

green fluorescent protein and provided compelling evidence

of mature TECs having a leading role in the regeneration

process in the post-ischemic kidney. The findings reported

Fig. 1 Distribution of stem/progenitor cells within the adult kidney. The different cell types involved are indicated. Studies conducted on mouse

or human kidney [47,1120] evidence a distributed presence of renal stem/progenitor cells

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by Humphereys et al. [26] substantially confirm these data,

elegantly demonstrating that no extratubular cells or intra-

tubular stem/progenitor cells contribute to the repair

process. They did not address, however, the possibility that

there may be distinct differences in the regenerative

potential among tubular cells.

So where or what does this regenerative potential of mature

epithelial cells come from? Developmental biology couldprovide the answer.

Epithelial-to-mesenchymal transition in developmental

processes

Several studies have shown that the repair of injured renal

epithelium begins when surviving tubular cells enter into an

activated proliferative state characterized by the reappear-

ance of mesenchymal markers detectable during nephro-

genesis [28]. After injury, therefore, the conversion of

TECs to a more mesenchymal phenotype suggests that anepithelial-to-mesenchymal transition does indeed occur.

Epithelial-to-mesenchymal transition (EMT) is a complex,

extreme manifestation of epithelial plasticity. It is now

widely recognized as a fundamental process in pathological

conditions (oncogenesis and fibrogenesis) as well as in

physiological events such as morphogenesis [29, 30].

During the development of the vertebrate embryo,

EMTs are a source of mesenchyme in various places and

stages throughout embryonic morphogenesis, but espe-

cially in the mesodermal domains [31]. It is currently

accepted that the epithelia precede both evolutionary and

ontogenetically the mesenchyme, and that the mesen-

chyme was originally an epithelial derivative [32]. Thus,

the epithelium is the earliest type of embryonic organiza-

tion, and the primitive epiblast represents the earliest

epithelial state in vertebrate development. The first EMT

occurs at gastrulation, when a subset of epiblast cells

undergo EMT and internalize to generate mesoderm and

endoderm, while those remaining in the epiblast become

ectoderm [33]. Mesoderm and endoderm contribute to

many tissues in the adult body that subsequently undergo

several rounds of EMT and MET (the latter being reverse

of EMT i.e. mesenchymal-to-epithelial transition). Imme-

diately after the primary mesenchyme has formed, most

mesoderm and all endoderm become reorganized in

primitive epithelia. These secondary epithelia give rise to

secondary mesenchymal cells in a series of EMTs. In

particular, intermediate mesoderm generates the nephro-

genic mesenchyme, which coalesces in tertiary epithelial

structures such as nephrones and nephric ducts [34].

In a very interesting model proposed by Perez-Pomares

et al. [31], the vertebrate embryo is considered as a two-

state system of which epithelium and mesenchyme repre-

sent the stable and unstable states, respectively. In partic-

ular, mesoderm might be seen as a cell layer capable of

oscillating between the plastic and exploratory behavior of

the mesenchyme and the stability of the epithelia. The

ability to go through cycles of epithelial and mesenchymal

states lends the mesoderm a greater plasticity, more

potential for innovation and a better control of three-

dimensional body organization [31]. The mesenchymederived from the chronologically earliest EMT has the

greatest developmental potential, which decreases progres-

sively in the subsequent EMTs. This model has a particular

appeal for explaining the kidneys almost exclusively

morphogenic process as well as its regenerative potential.

In this setting, some of the developmental potential of the

primitive epithelium may remain in the definitive epitheli-

um derived from the mesenchyme (as in renal epithelial

cells), enabling cells to respond quickly to micro-

environmental changes. Indeed, very recently, two papers

have proposed that EMT could be the process driving

mammary epithelial cells [35] and glomerular parietalepithelial cells [36] to adopt stem cell characteristics.

These remarks could suggest that the kidneys need for a

real stem cell compartment is less important than the cells

phenotypic flexibility, as in other mesenchymal tissues. The

plasticity of TECs resembles that of adult mesenchymal cells,

which are long-lived and constantly exposed to the extracel-

lular matrix. The matrix provides a microenvironment that

helps the cells to maintain a differentiated or undifferentiated

state, i.e. the cell plasticity of this tissue seems to serve the

same purpose as the multipotency of adult stem cells

without the need for a real stem cell compartment [37].

The renal papilla as a stem cell niche

Oliver et al. [38] found a high proliferation rate in the upper

papilla, especially laterally, adjacent to the urinary space of the

normal kidney. By staining renal tissue sections from adult 1-

yr old rats with Ki67, they found positive cells in the upper

papilla with a frequency that was low (2.6% of all cells), but

significantly higher than elsewhere in the kidney. The same

Authors also found LRCs with several characteristics of adult

stem cells in the papillary interstitium and collecting duct, that

were able to generate new cells in the normal adult kidney.

They suggested that, during normal homeostasis, interstitial

LRCs or their immediate progeny migrate to the upper papilla

and form a compartment of rapidly proliferating cells that may

have a role after acute injury.

Dekel et al. [6] also found non-tubular Sca-1+ multi-

potent/progenitor cells in the adult mouse kidney, located

mainly in the papillary interstitial space. These cells were

located in the outermost part of the papilla, close to the

tubules and sometimes adjacent to the tubular basal surface,

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and they displayed some features of the papillary stem cells

isolated by Oliver at al. [38].

Unlike other areas of the kidney, the renal papilla displayed

no apoptosis after the ischemic insult, so the presence of

numerous LRCs within a restricted area of the papilla base

and the rapidly-proliferating cells in the upper papilla (which

can migrate to other parts of the kidney more susceptible to

the low oxygen tension) evoke the architectural arrangementof the stem cell compartments of highly-regenerative organs

such as the epidermis. Stem cells are usually located in deep,

narrow tissue niches, where the proliferative phenomena

behind self-maintenance take place. The transient zone (rich

in amplifying precursor cells) and the differentiated cells in

various stages of maturation lie respectively in the progres-

sively more distal cell layers.

The stem cell niche as a functional entity

The concept of stem cell niche is changing. The mere

location of stem cells is not sufficient to define a niche,which must have both anatomical and functional dimen-

sions [39]. This issue is particularly important as new stem

cell sites come to light. Accumulating data have challenged

the conviction that heterologous cells must necessarily

occur in niches, suggesting that for some stem cells the

niche may consist of extracellular matrix and other non-

cellular constituents that could regulate their function [39].

Both paracrine and metabolic factors could serve function-

ally as a niche, which could also be seen as a dynamic

structure capable of being formed anew and responding to

exogenous signals via a sensing system possibly consisting

of the nervous or circulatory systems. Indeed, there is a

growing body of data to indicate the perivascular site as a

stem cell niche [4042]. Whether the components of the

vasculature are niche cells (i.e. cells interacting with stem

cells) or stem cells remains to be seen.

The perivascular mesenchymal stem cell niche hypothesis

Multipotent mesenchymal stromal cells (MSCs), typically

defined as adherent fibroblastoid cells capable of differen-

tiating into osteoblasts, adipocytes and chondrocytes in

vitro, have been found to reside within the connective tissue

of most organs, including the kidney, where they have been

isolated from glomeruli and the kidney as a whole [40].

Immunophenotyping indicates that MSC populations orig-

inating from different sources share numerous surface

markers, e.g. CD29, CD44, and express SMA, a vascular

smooth muscle cell marker, pointing to a relationship with

perivascular cells [43].

These findings have prompted the suggestion that MSCs

may derive from perivascular cells. Pericytes are good

candidates to represent the MSC population within organs [41].

In resting tissues, pericytes and endothelial cells (EC) are

quiescent, slow-cycling cells, but in the angiogenic stage

they show a highly-proliferative potential, a capacity for

self renewal, and the ability to generate daughter cells, thus

behaving like adult stem cells. Pericytes isolated from

different tissues display a marked plasticity and are able to

differentiate into osteoblasts, chondroblasts, fibroblasts,

pre-adipocytes [42]. It is also worth mentioning thatpericytes have been involved in vascular and ectopic

calcification [44]. That adult organ MSCs might be

pericytes or pericyte-like cells is also supported by the fact

that they can share some markers, such as CD146, 3G5

[45]. Taking these findings as a whole, we could conclude

that the MSC compartment extends through the post-natal

body as a result of its perivascular location.

The microvasculature of the renal papilla is particularly

rich in pericytes, subendothelial cells that regulate micro-

vascular integrity in the peritubular capillary network and

give the descending vasa recta (the arteriolar segments

supplying blood to the medulla) their contractile function.Thus in the papilla might reside that MSC compartment

linked to the perivascular niche. Mesenchymal stromal stem

cells have repeatedly been isolated from the kidney [14,

4649]. Very recently Lee et al [20] have presented

evidences that progenitor cells (MKPC) with mesenchymal

stromal stem cell properties reside in the mouse kidney

interstitium of the medulla and papilla in close association

with endothelial cells. Indeed, all stem/progenitor cells

isolated from the papilla expressed markers of MSCs such

as CD 29 and showed positivity forSMA [5,6,20] which

is considered a typical marker of perycites pointing to a

possible relationship with papillary vascular pericytes [50]

(Fig. 2).

Could pericytes represent a subpopulation of these

MSCs in the kidney, and in the papilla in particular? Is

there an ancestor of the MSC natively associated with the

perivascular cells? Once again, the answer comes from

developmental biology.

Embryonic origin of stromal and vascular kidney cells

The mammalian kidney develops in three waves, only the last

of which (the metanephros) continues to exist as the adult

kidney. All three embryonic kidneys arise from the meso-

derm, one of the earliest tissues to develop in the embryo.

Nephrogenesis involves a carefully-controlled series of

morphogenic and differentiation events that start with the

interaction between two different primordial epithelial and

mesenchymal tissues both originating from the intermediate

mesoderm, i.e. the ureteric bud of Wolffian derivation grows

and invades the metanephric blastema. Factors secreted by the

ureteric bud induce this mesenchyme first to form clusters and

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then to change into epithelium and the specialized structures

constituting the nephron. The induced mesenchyme in turn

sends signals back to the ureteric bud to make it divide and

grow (reviewed in [51]). This process of reciprocal induction

proceeds in an orderly manner, from the deep to the outer

cortex, producing branches of the collecting tree and neph-

rons, progressing from the glomerulus to the distal tubule.

The development of most tubular organs relies on signaling

between epithelial and mesenchymal stromal progenitor

populations. These two populations often derive from different

germ layers that are specified during gastrulation, well in

advance of organ condensation [52]. In kidney development,

however, the mesenchymal and epithelial lineages both derive

from the intermediate mesoderm. Moreover, the branching

morphogenesis of most tubular organs arises from pre-existing

epithelial sheets or tubules, whereas in the kidney not only do

the mesenchymal cells of metanephric blastema generate all

the epithelia of the nephron through mesenchymal-to-

epithelial transition (MET), they also drive the branching of

the ureteric bud. The metanephric blastema (also known as

metanephric mesenchyme) is composed of a non-

homogeneous population of cells that sends signals to the

Wolffian duct, which gives rise to the ureteric bud in response

[53]. One of the fundamental questions of kidney develop-

mental biology is how many cell lineages there are in the

metanephric blastema before and after it is induced by the

ureteric bud. The traditionally held view is that mesenchymal

cells that do not regain an epithelial state through MET may

differentiate and give rise to connective tissue and stromal

cells [54].

To date, the origin of renal stromal cells has remained

unknown, though there is some evidence of these cells

developing from a separate cell lineage within the meta-

nephric blastema [55]. Using fate mapping techniques,

Guillaume et al. [52] very recently demonstrated that large

populations of renal stromal cell originate from a different

part of the mesodermthe paraxial mesodermthus

indicating that renal development (like that of all other

tubular organs) depends on the integration of progenitors

from different embryonic tissues into a single rudiment. It is

noteworthy that bones, skeletal muscle and tendons

originate from paraxial mesoderm. In this light, the ability

of MSCs to differentiate into osteoblasts and chondrocytes

must be a commitment received in the very early

embryological stages.

During the reciprocal inductive stage of metanephric

development, two distinct regions of metanephric mesen-

chyme are morphologically distinguishable, i.e. the cap

mesenchymal cells, which are Pax2 positive and will form

nephrons; and the region peripheral to the cap mesenchyme,

where cells expressing Foxd1 may represent stromal progen-

itor cells, and cells that are Foxd1-negative, but Six2-, Gdnf-

and Cited1-positive, may be mesenchymal stem or progenitor

cells. When branching of the ureteric bud has begun and

nephron induction takes place, the stromal cells surrounding

the branches of the ureteric bud and the induced nephrons

Fig. 2 a The different stem cell

types isolated from the papillary

interstitium are indicated, fig-

ures were drawn from the

articles cited within parethesis. b

Histology of the renal papilla,

EE staining, 200x magnifica-

tion. c -smooth muscle stain-

ing of the renal papilla, 200X

magnification

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constitute the primitive interstitium [56] (Fig. 3). By late

gestation, a secondary interstitium is created with two distinct

populations, the cortical stroma and the medullary stroma,

which then differentiate to form the adult kidney interstitium,

with the cortical interstitium comprising fibroblasts and

lymphocyte-like cells, and the medullary interstitium mainly

comprising lipid-laden interstitial cells, lymphocyte-like cells

and pericytes [56,57].

From these studies, one might argue thatwhatever

their true origin (from the intermediate or paraxial meso-

derm)the mesenchymal stromal cells contain different

cell lineages, including the precursor of the vasculature.

Angioblasts (individual endothelial progenitors) are

integral to the development of the glomerular tuft, and they

are identified in the developing kidney because they

express typical vascular markers, such as vascular endo-

thelial growth factor receptor 2 (VEGFR2). Although

metanephric mesenchyme contains VEGFR2-positive cells

from the early stages of development, cross-species

transplantation studies have suggested that extrarenal cells

also contribute to the glomerular vasculature [58].

Mesoangioblasts are considered vessel-associated meso-

dermal stem cells. Originally identified in the mouse

embryonic aorta, similar but not identical cells have been

identified in postnatal vessels of several organs, such as the

skeletal muscle and heart. Interestingly, they have in common

the expression of endothelial and/or pericyte markers [59].

Mesangioblasts may be the ancestors of postnatal vessel-

associated progenitors, such as pericytes [60].

Taken together, these findings may indicate: 1) that MSCs

andpericytes are identical in that they have a common ancestor

and share the same phenotypic markers; 2) that the distribution

of MSCs throughout the body post-natally is related to their

existence in a perivascular niche; and 3) that interstitial MSCs

might reside in the microvasculature in the kidney papilla.

Conclusion

Our growing understanding of the cellular and molecular

mechanisms behind kidney regeneration and repair pro-

cessestogether with a knowledge of the embryonic origin

of renal cellsshould induce us to bear in mind that the

kidneys need for a real stem cell compartment is less

important than the cells phenotypic flexibility. One of the

major tasks of regenerative medicine will be to disclose the

molecular mechanisms underlying renal tubular plasticity

and to exploit its biological and therapeutic potential.

On the other hand, data are emerging that capillary and

microvessel walls all over the body may harbor a reserve of

MSCs; in the kidney, this might be located in the papilla.

The perivascular niche hypothesis fits well with the

evolving concept of the stem cell niche as an entity of

action. It is its dynamic capability that makes the niche

concept so important and essential to the feasibility of

regenerative medicine.

Acknowledgements This study was supported by Grant No.

CPDA085494 from the University of Padua.

Conflicts of interest The authors declare no potential conflicts of

interest.

Fig. 3 Schematic representation of renal development during em-

bryogenesis showing the different cellular components involved in theprocess of nephrogenesis and collecting duct branching. Figure is

based on Figure 4 in the Journal of Cellular and Molecular Medicine

by authors Anglani F, Forino M, Del Prete D, Tosetto E, TorregrossaR., DAngelo A [51]

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