Bone Marrow Stem Cells Contribute to Healing of the Kidney
Richard Poulsom*,
Malcolm R. Alison,
Terry Cook,
Rosemary Jeffery*,
Eoin Ryan*,
Stuart J. Forbes,
Toby Hunt*,
Susannah Wyles* and
Nicholas A. Wright*,
*Histopathology Unit, Cancer Research UK, London Research Institute, London, United Kingdom; Department of Histopathology, Imperial College, Hammersmith Campus, London, United Kingdom; Department of Medicine, Faculty of Medicine, Imperial College, St. Mary’s Hospital, London, United Kingdom; and Bart’s and the Royal London Hospitals, Queen Mary College, London, United Kingdom.
Correspondence to Prof. Richard Poulsom, Histopathology Unit, Cancer Research UK, London Research Institute, 44 Lincoln’s Inn Fields, London, WC2A 3PX, UK; Phone: +44-(0)-20-7269-3538; Fax: +44-(0)-20-7269-3491;
ABSTRACT. A variety of recent studies support the existenceof pathways, in adult humans and rodents, that allow adult stemcells to be surprisingly flexible in their differentiation repertoires.Termed plasticity, this property allows adult stem cells, assumeduntil now to be committed to generating a fixed range of progeny,on relocation to switch to make other specialized sets of cellsappropriate to their new niche. Cells normally present withinthe bone marrow seem particularly flexible and are able to contributeusefully to many recipient organs. In studies of the liver,bone marrow–derived cells are seen with specialized structuraland metabolic adaptations commensurate with their new locations,and these may be abundant, even sufficient, to rescue recipientmice from genetic defects and with evidence that they have proliferatedin situ. In the kidney, several studies provide evidence forthe presence of "reprogrammed" cells, but in most, it remainspossible that cells arrive and redifferentiate but are no longerstem cells. Nevertheless, that appropriately differentiatedcells are delivered deep within organs simply by injection ofbone marrow cells should make us think differently about theway organs regenerate and repair. Migratory pathways for multipotentialcells could be exploited to effect repairs using an individual’sown stem cells, perhaps after gene therapy. This concept makesit clear that a transplanted organ would in time become affectedby the genetic susceptibilities of the recipient, because ofphenotypes that are expressed when trafficking cells incorporateand differentiate. E-mail: richard.poulsom@cancer.org.uk
Some 30 yr ago, it was suggested that there were probably circulatingendothelial precursor cells, derived from the bone marrow thatcontributed to the repair of renal vessels after transplantation(1), yet until recently it had not been appreciated that bonemarrow contributed a variety of cells to tissues in severalorgans. This contribution has become recognized with the adventof robust methods for tracking cell lineage in routine histologyspecimens.
In adult organisms, each tissue and organ is generally acceptedto contain a small subpopulation of cells capable of self-maintenance,of indefinite proliferative potential and with the ability togive rise to a large family of descendants with defined spectraof specialization (multipotential stem cells) (2–6). Thelocation of the stem cell compartment(s) in the adult kidneyis not clearly defined. In kidney development, it is recognizedthat single metanephric mesenchymal stem cells can generateall of the epithelial cell types of the nephron (other thanthose of the collecting ducts), but it is unknown whether suchstem cells persist in adult life (7). Experiments seeking label-retainingcells and proliferative compartments suggest that in the glomerulus,the most frequently labeled cells were endothelial and thatthe epithelia lining Bowman’s capsule were labeled moreoften than cells in the tuft, with podocytes almost never labeled(8).
The adult mammalian kidney has some ability to repair. Tubularcells can divide and tubules may regenerate after injury, whichmay involve epithelial-mesenchymal transition (EMT; outlinedbelow). In addition, it now seems that the bone marrow actsas a renal stem cell compartment. Bone marrow has recently beenrecognized as a third stem cell compartment for the liver, afterhepatocytes and cholangiocytes (9–12). Perhaps the "normal"physical separation of hematopoiesis from renal function inadult mammals prevents the generation of new nephrons, whereasin some fish, hematopoiesis occurs in the kidney and new nephronscan be formed (13).
Bone marrow contributes to maintenance and repair of severalcompartments of the kidney, including the endothelium, interstitium,epithelium, and the mesangium.
Maintenance of Renal Endothelium
Early observations based on counts of Barr bodies led to thehypothesis that endothelial replacement in grafted organs isencouraged where endothelial damage is severe (1) and to a secondhypothesis that extensive acute damage requires repair by hostcells, whereas less severely damaged grafts could be restoredby endothelial continuity from surviving donor endothelial cells(14). More recently, Lagaaij et al. (15) suggested that theextent of replacement of endothelial cells lining small renalvessels was related to the severity of vascular rejection, assix of seven grafts affected by vascular rejection showed >33%recipient-derived endothelial cells, whereas just 2 of 13 patientswithout evidence of rejection showed an extensive endothelialrecolonization. We have seen occasional male endothelial cellsin female renal allografts but had focused on epithelium (16).However, Andersen et al. (17) studied 45 renal biopsies from40 gender-mismatched transplant patients suspected of developingacute rejection and found no evidence of revascularization bythe recipient, even in 4 cases in which the transplant failed.
The origin of the glomerular endothelium in transplanted kidneysis less clear. It might be expected that migration and integrationof recipient endothelial precursor cells (EPC) should occurin the glomerulus, yet Sinclair (14) considered glomeruli tobe unaffected, Lagaaij et al. did not comment on them (15),and Andersen et al. (17) found no recipient endothelium; onlyin the mouse is there firm evidence that whole bone marrow contributesto glomerular endothelium (18).
Epithelial Mesenchymal Transitions and Renal Repair
In the kidney an EMT between the phenotype of epithelial cellsand fibroblasts (both being generated originally from the primitivemetanephric mesenchyme) is seen as a response to a breach ofthe tubular basement membrane (19). In various models, epithelialcells are seen to acquire markers of fibroblasts or myofibroblastsand adopt a fusiform morphology; in interstitial fibrosis, cellsare seen with a fibroblastic morphology, yet they bear epithelialmarkers. Key effector molecules in EMT are TGF-1, EGF, and fibroblastgrowth factor-2 (20–22), with the extracellular matrixalso affecting cell phenotype (23). EMT seems restricted toregions where the basement membrane is damaged, with the cellsmost myofibroblastic in phenotype seen where the tubular basementmembrane was extensively damaged (24). These observations andothers on cultured cells are concordant with the hypothesisthat the epithelium adopts a fibroblastic morphology beforeproliferating and perhaps before helping to repair the basementmembrane. Sun et al. (25) examined rat kidneys after uranylacetate induced tubular necrosis and considered that repairoccurred without movement of cells from the interstitium intothe denuded tubules, yet they observed proliferation of flattenedcells lining the regenerating tubules that expressed vimentin,like myofibroblasts.
A broader hypothesis is that the EMT process is reversible,with some of the myofibroblasts being of extrarenal, perhapsnormally bone marrow in origin. There is some support for thisview. Transplantation of male whole bone marrow into femalerecipients is followed in the small and large intestine by progressiveconversion (to male) of most of the smooth muscle actin–expressingmyofibroblast population surrounding the crypts (26).
In our studies of whole bone marrow transplants in mice, weobserved marrow-derived interstitial cells and renal tubularepithelial cells (16). As illustrated in Figure 1, these werein general scattered in tubules, although small clusters didoccur. In human renal transplants in which female kidneys weregrafted into male recipients, we noted male tubular cells expressingthe epithelial marker CAM 5.2 (16). A bone marrow contributionto renal tubular epithelium has also been reported, in abstractform, by Lin et al. (27), who used -galactosidase as a markerof origin.
Figure 1. (Top) Sections of kidney from a female mouse after bone marrow ablation and grafting with male bone marrow. Y chromosomes were detected by hybridization in situ to a specific DNA paint and revealed immunohistochemically as brown dots. Tubular epithelium was demonstrated by immunohistochemistry using an antiserum to cytochrome P450 1A2 generating a blue reaction product. Marrow-derived tubular epithelial cells are marked with arrows and presumed inflammatory cells with asterisks. (Bottom) Combined immunohistochemistry for vimentin (red reaction product) and indirect ISH for Y chromosomes (brown reaction product); co-localization in the glomerulus is suggestive of a marrow-derived podocyte phenotype.
Considering glomeruli, we have described marrow–derivedcells that seemed to be podocytes (16), based on their locationand immunoreactivity for vimentin. As illustrated in Figure 1,these cells were seen to have a brown-stained Y chromosomewithin a nucleus located in a vimentin-positive cell. An additionalstrand of evidence is presented in Figure 2, in which dual fluorescencein situ hybridization for X and Y chromosomes has been carriedout on a histologic section of human female kidney that hadbeen transplanted into a male recipient. The vast majority ofassessable cells were female (two green-fluorescent X chromosomes).More detailed examination of a region of the glomerulus shownrevealed two cells apparently with pairs of X and Y chromosomes;this region was scanned serially in the z-axis and a "panorama"of 64 slices generated to help visualize the arrangement ofsignals more clearly. This process indicated that there areindeed cells at the periphery of the glomerular tuft with 2X and 2 Y. One possibility is that these are nuclei of malepodocytes; binucleate podocytes have been reported in 6 of 164cases of diseased human kidney, although mitotic podocytes arevery rare (28). The possibility that these nuclei result fromfusion or imminent division of two male cells (both XY) cannotbe excluded at this stage.
Figure 2. Dual fluorescence in situ hybridization to detect male cells within a histological section of female donor kidney biopsy taken from a male recipient. (Top) A frame from a confocal panorama rotation of a Z-series of one glomerulus, showing signals from green fluorescence (X chromosome probe), red fluorescence (Y chromosome probe), and combined images; pairs of green dots are clearly seen over several nuclei establishing their female (donor) origin. The autofluorescent debris indicated by an arrow is visible at higher magnification. (Bottom), which shows frames from a further data set of the same region; two adjacent sets of nuclei are seen to possess two X and two Y chromosomes indicating their recipient origin.
Grimm et al. (29) also reported evidence for host-derived mesenchymalcells in renal transplants that were experiencing chronic rejection,but did not describe the generation of tubular cells. Andersenet al. (17) noted that tubular and glomerular cells remainedof donor origin in transplanted kidneys even 10 mo after transplantation,and no donor-derived renal tubular epithelial cells were seenin any of the 5 mice grafted by Krause et al. (30), perhapsas a result of the use of sorted hematopoietic stem cells ratherthan whole marrow cells.
Bone Marrow Contribution to the Glomerular Mesangium
Studies using enhanced green fluorescence protein (eGFP)-transgenicrats revealed that the bone marrow makes a significant long-termcontribution to the mesangial cell population (31). In mice,one of the most significant reports of bone marrow–derivedcells contributing to renal repair is that of Cornacchia etal. (18), who demonstrated that bone marrow from mice with aninherited glomerular mesangial sclerosing defect transferredthe disease phenotype; the morphology and matrix metalloproteinaseexpression levels were due to generation of endothelial andmesangial cells from the donor bone marrow. Another study revealingthat bone marrow–derived cells can affect the progressionof renal disease is that of Yokoo et al. (32), who used engineeredbone marrow to deliver to the glomerulus cells expressing agene that reduced susceptibility to experimental Goodpasturesyndrome, although they did not seek to establish whether any"plasticity" had occurred.
Which Bone Marrow Cells Contribute to Renal Repair?
Adult bone marrow contains hematopoietic stem cells (HSC) andmesenchymal stem cells (MSC), which may derive from a commonprimitive blast-like cell precursor able to differentiate alongMSC or HSC potentials (33). These two populations both are viablewhen whole bone marrow is aspirated and immediately transplantedby injection intravenously into recipient irradiated mice, yetthey are seen to have different potentials; MSC isolated byadhesion to plastic or other means are able to contribute tobone, cartilage, and cardiac muscle but not to blood or liver,whereas HSC isolated by cell sorting can contribute to liverand cardiac muscle and vasculature (see review (34)).
It is unclear whether HSC or MSC or both are responsible forthe cellular progeny found in the kidney after transplantationof whole bone marrow, although sorted HSC were reported to beable to contribute to tubular epithelium (27). It is also notknown in renal transplantation whether the recipient cells thatengraft are derived from bone marrow or other circulating populations.
The ability of a cell to act as a stem cell is regulated toa considerable extent by the environment forming the niche whereit resides (35). In the development of melanocytes, for example,it seems that melanoblasts (generally considered to be committedprecursors and no longer stem cells), when given the opportunityto occupy vacant niches, revert to a stem cell state (36). Nichesmay be defined by a combination of matrix-bound and solublefactors that can be altered experimentally. Factors presentwithin a cell line–conditioned medium regulate the programmingof early primitive ectoderm-like cells, significantly changingthe repertoire of differentiation possible from these cellsin a reversible way (37). Adult mouse neural stem cells injectedinto an early embryo contribute to the developing kidney (38),so adult stem cells may be reprogrammed to differentiate intorenal cells. Thus, it may be a reasonable hypothesis that circulatingstem cells occupy tissue-specific niches vacated after damageand then adopt the lineage restriction appropriate to theirnew environment. Whether this engraftment or subsequent expansioncould be modified by exogenous growth factors needs to be tested.One candidate is hepatocyte growth factor, which has been shownto offer renal protection in allograft nephropathy in rats (39)and is also recognized as an agent involved in the differentiationof metanephric mesenchymal cells into epithelial precursorsof the nephrons (40).
In the kidney, there is no recognizable stem cell zone and thereforeno pattern of replacement possible to recognize that would establishthat engrafted cells are operating now as local stem cells,rather than isolated reprogrammed cells. What would be usefulis a mechanism to reveal clonal expansion, whereby progeny ofindividual cells could be recognized. Demonstration of thiswould, ideally, require the isolation and transplantation ofsingle cells that self-renew and produce a family of descendantsthat eventually become fully functional; these robust criteriahave been met for the liver, in a model in which the progenyhad a selective advantage (41). However, some commentators haveadded that this phenomenon should be shown to occur "naturally"in organs, not forced to undergo organ degeneration before acceptingthat stem cells jump a lineage boundary (42). Clearly, it isdifficult to track cells without intervention, and most of thestudies to date involve damage consequent on ablation of bonemarrow by irradiation or chemical means or the traumas of surgeryand rejection, whereby organs have been transplanted then studiedsome time later.
A counter argument is that a degree of organ damage is essentialto allow transdifferentiation or stem cell plasticity to takeplace at recognizable levels. Kleeberger et al. (43) found thatcholangiocyte differentiation occurred earlier and more frequentlythan hepatocyte differentiation from circulating cells and thathepatocytes were formed more commonly when there was recurrenthepatitis. They used an elegant laser capture microdissection/PCRamplification method to establish whether specific cells wereof donor or recipient origin. It may be that migration of bonemarrow stem cells throughout the body acts essentially as aback-up system, able in extremis to augment an organ’sintrinsic regenerative capacity.
The origin of cells seems clear in studies in which whole orsorted bone marrow cells have been transplanted and a markersuch as eGFP or -galactosidase has been used for lineage tracing,but what of studies in which female organs have been examinedat times after transplantation into male recipients and theY chromosome has been used as a lineage marker? Transfer offetal cells across the placenta does occur (e.g., (44)), andlong-term male microchimerism of blood mononuclear cells isrecognized (45). So might the male cells recognized in femaleallografts be from earlier pregnancies. In some studies of liverengraftment, this mechanism has been considered and excluded(9,43), but it remains a possibility for the kidney.
Stem Cell Plasticity, Transdifferentiation, or Fusion Confusion?
Earlier this year, concerns were raised that the methods usedto show that certain adult stem cells, particularly from thebone marrow and central nervous system, can jump lineage boundariesmay be flawed, e.g., if reliance had been placed solely on theappearance of Y chromosome-positive cells in a female recipientor even if markers such as -galactosidase or GFP had been used.Two publications suggested that the development of seeminglynormal differentiated cells expressing a new marker might simplybe due to the fusion of bone marrow cells with preexisting differentiatedcells in the host’s organs (46,47). Cell fusion eventswere shown to be possible, but at very low frequency (1:100,000cells) in tissue culture systems, not in vivo. Furthermore,the possibility that fusions (or heterokaryons) account forall instances of transdifferentiation or plasticity is at oddswith a number of observations:
When highly purified hematopoieticstem cells from male Rosa26bone marrow were used to rescuefemale mice deficient in fumarylacetoacetate hydrolase (41),discrete nodules of -galactosidase–positiveliver tissueformed in the liver. The nodules had normal histologyand werenot teratoma-like (as seen after fusion events 46)).
The thyroidof women with thyroid disease frequently containmale cellsof presumed fetal origin, yet these were seen topossess justone X and one Y chromosome (48), rather than theXXXY predictedinitially after fusion.
Hematopoietic stem cells are abundantin cord blood and arefound in peripheral blood, especiallyafter exercise: if fusionevents were common and without disadvantage,then we all shouldhave large numbers of polyploid cells inmany organs. This hasnot been reported outside the liver, wherepolyploidizationdoes occur on a large scale—as a resultof binucleatecells segregating on the same mitotic spindle.
Therapeutic grafting of female patients with G-CSF–mobilizedperipheral blood stem cells from male donors produced a varietyof male cells, including new hepatocytes in the liver, but allthose shown had one X and one Y chromosome (49).
Until studies show that heterokaryon formation actually occurswhen adult stem cells "transdifferentiate" in vivo, extrapolationsfrom rare events involving cultured embryonic stem cells arepremature.
There is now a large body of evidence indicating that organ-specificstem cell populations need not rely entirely on their own resourcesfor maintenance and repair. Perhaps a key factor in the generationof self-renewing clones in the new tissues is the exposure to—andsuccessful occupation of–niches emptied by damage, withthe local environment of the niche defining the cell repertoirethat will be produced.
Extraordinary claims require extraordinary proof, and some haveasked for a higher standard of evidence; requiring "a clonalapproach" (50) or demonstration of "a robust, sustained multi-lineageengraftment and functional activity representative of multiplephenotypic characteristics of the converted cells to show thatfull conversion has occurred" (42). These criteria, put simply,are needed because showing partial repopulation of an organwith cells that have come to resemble their neighbors is notthe same as showing a functional competence as diverse and broadas that expected of the indigenous population, yet this is whatwill be needed for tissue regeneration and for gene therapystrategies that rely on adult stem cell plasticity. We willneed clonal expansion to yield all of the cell types normallyproduced, and only those, together with appropriate responsesto the usual demands of growth, adaptation, and repair. So far,the experiments of Lagasse et al. (41,51) are closest to answeringall criticisms, yet researchers who are working on other organshave shown transplanted bone marrow cells to effect a degreeof rescue from or transfer of pathology in bones (52), skeletalmuscle (53), central nervous system (54), and kidney (18). Froma practical point of view, therapies may be possible soon, butunderstanding the risks will take longer.
Acknowledgments
We are grateful to the following individuals for help in carryingout aspects of this research: Kairbaan Hodivala-Dilke, SobanaNavaratnarasah, Charles Pusey, Robin Edwards, S. Agarwal, E.Clutterbuck, G. Gaskin, R. Lechler, E. Lightstone, A. Warrens,and G. Williams.
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J.J. Mao, W.V. Giannobile, J.A. Helms, S.J. Hollister, P.H. Krebsbach, M.T. Longaker, and S. Shi Craniofacial tissue engineering by stem cells.
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M. Karl, M. Berho, J. Pignac-Kobinger, G. E. Striker, and S. J. Elliot Differential Effects of Continuous and Intermittent 17{beta}-Estradiol Replacement and Tamoxifen Therapy on the Prevention of Glomerulosclerosis: Modulation of the Mesangial Cell Phenotype in Vivo
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A. Leri, J. Kajstura, and P. Anversa Cardiac Stem Cells and Mechanisms of Myocardial Regeneration
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A. Shimizu, Y. Masuda, T. Mori, H. Kitamura, M. Ishizaki, Y. Sugisaki, and Y. Fukuda Vascular Endothelial Growth Factor165 Resolves Glomerular Inflammation and Accelerates Glomerular Capillary Repair in Rat Anti-Glomerular Basement Membrane Glomerulonephritis
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Department of Medicine, Faculty of Medicine, Imperial College, St. Mary’s Hospital, London, United Kingdom; and 
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Abstract
Introduction
1, EGF, and fibroblast growth factor-2 (20–22), with the extracellular matrix also affecting cell phenotype (23). EMT seems restricted to regions where the basement membrane is damaged, with the cells most myofibroblastic in phenotype seen where the tubular basement membrane was extensively damaged (24). These observations and others on cultured cells are concordant with the hypothesis that the epithelium adopts a fibroblastic morphology before proliferating and perhaps before helping to repair the basement membrane. Sun et al. (25) examined rat kidneys after uranyl acetate induced tubular necrosis and considered that repair occurred without movement of cells from the interstitium into the denuded tubules, yet they observed proliferation of flattened cells lining the regenerating tubules that expressed vimentin, like myofibroblasts. 
1:100,000 cells) in tissue culture systems, not in vivo. Furthermore, the possibility that fusions (or heterokaryons) account for all instances of transdifferentiation or plasticity is at odds with a number of observations: 
