The traditional view that organs have only limited regenerativecapacity has been challenged in recent years as adult bone marrowstem cells as well circulating progenitor cells have been identifiedto retain the plasticity to participate in neovascularization,a process so far believed not to be possible after birth. Anorgan that is damaged by ischemia causes the release of cytokines;these act via the flowing blood and stimulate the bone marrow,which then mobilizes progenitor cells to the blood and directsthem to adhere to and migrate into the damaged organ. Thus,these progenitor cells most likely constitute a natural repairmechanism that counteracts degenerative or aging processes.On the basis of encouraging experimental data, first clinicaltrials have been established to demonstrate the safety and thefeasibility of progenitor cell therapy in case of peripheralartery disease or myocardial infarction. Trials investigatinginjection of bone marrow or circulating progenitor cells intothe coronary artery after an acute myocardial infarction notonly demonstrates safety of the procedure but also gave hintstoward efficacy. Nevertheless, these findings have to be validatedby subsequent larger, prospective, randomized, controlled trials.There are also potential topics in nephrology, where modificationof progenitor cell activity might be of benefit, such as renalischemic disease, glomerular disease, and renal transplant vasculopathy.Finding a way to integrate the principle of progenitor cellaction into therapeutic efforts might provide a completely newtherapeutic strategy that not only attempts to retard diseaseprogression but furthermore targets to regenerate damaged organs.
Until recently, it was thought that the heart does not possessa regenerative capacity, because adult cardiomyocytes are terminallydifferentiated and have lost their capacity to renew. The onlyresponse to an increased functional demand was seen to be hypertrophyof cardiomyocytes. However, this view has been challenged byfindings in patients after heart transplantation with a sex-mismatchtransplantation (1,2): In myocardial biopsies of male recipientpatients who received a female donor heart, Y chromosomes werefound, indicating that recipient cells were coming from outsidethe donor heart, migrating, and integrating into the transplantedheart. Those Y chromosomes containing cells were identifiedas both cardiomyocytes as vascular cells (e.g., endothelium).
There is evidence that the cells regenerating the heart arecoming from the bone marrow as demonstrated in sex-mismatchbone marrow transplant patients who undergo a myocardial biopsy(3). Similar findings have been obtained for the kidneys. Poulsomet al. (4) found Y chromosomes in renal tubules and glomeruliin female mice that received a male bone marrow transplant.Before these findings, Asahara et al. (5) already identifiedprogenitor cells with an endothelial phenotype (endothelialprogenitor cells) circulating in the blood. It is interestingthat the amount of peripheral endothelial progenitor cells isreduced with increasing number of cardiovascular risk factors(6), and, in contrast, increased colony-forming capacity ofendothelial progenitor cells is associated with improved endothelialvasodilator function (7), an index of vascular integrity thatpredicts a favorable cardiovascular prognosis (8).
Recent evidence indicates that the plasticity of adult stemor progenitor cells (more differentiated stem cells) that arereleased from the bone marrow is much larger than previouslysuspected (9,10). Traditionally, it has been thought that stemcells are committed to certain cell lines (tissue specificity)and, with increasing degree of maturation, lose their abilityto dedifferentiate (return to a more immature form) or to transdifferentiate(changing the path to another cell line).
It is intriguing to speculate that progenitor cells that circulatein the blood may be part of a physiologic repair system designedby nature to repair damaged organs (11). However, this regenerativemechanism is most likely adjusted to a low-grade and slow injury,probably as a counterweight for degenerative or aging processes.However, in case of a "mass destruction," such as an acute myocardialinfarction, the physiologic repair capacity is obviously byno way sufficient.
However, ischemia is a trigger for the release of progenitorcells from the bone marrow, leading to the release of messengermolecules (growth factors, cytokines) that circulate in theblood, perfusing also the bone marrow (e.g., erythropoietinor granulocyte colony-stimulating factor) (12). These stimulitake part in cleavage and mobilization of progenitor cells fromthe bone marrow, entering the blood pool. When passing ischemictissue, these progenitor cells are extracted and targeted toadhere and migrate by the receptors and messenger proteins releasedfrom the ischemic tissue, thereby also taking part in neovascularization.
Indeed, it has been shown experimentally for the heart (13–16)as well as for the kidney (17) that progenitor cells from thebone marrow (genetically marked for the possibility to stainfor histology) integrate after an ischemic injury (Figure 1).In line, these studies demonstrated that animals that were treatedwith progenitor cells experienced a functional improvement inorgan function such as reduced left ventricular (LV) remodelingand improved LV function in the case of the heart (14) or reducedurea increase after renal artery ligation in the case of thekidney (17).
Figure 1. Experimental setting to test capacity of progenitor cells released from the bone marrow to regenerate damaged organ, as used by Kale et al. (17). First, bone marrow transplantation was performed with cells, genetically marked by -gal. Then, renal artery occlusion was performed to induce ischemia, which releases messenger stimuli to mobilize progenitor cells from the bone marrow. By staining for -gal, bone marrow–derived cells can be identified in the kidney and histologically characterized.
However, despite the finding that bone marrow cells transdifferentiateinto premature parenchymatous or vascular (endothelial) cellsor fuse with mature cells, there is an ongoing debate aboutthe extent and the importance of these observations (18–20).Other potential therapeutic effects of progenitor cells includeproduction of cytokines such as vascular endothelial growthfactor, stromal cell derived factor 1 (SDF-1), hepatocyte growthfactor, or IGF-1 (21). Thus, therapy with progenitor cells mightamplify biochemical signaling cascades that contribute to regenerationof organs, especially by neovascularization.
The regenerative capacity of progenitor cells might be usedtherapeutically if it is possible to intensify the effect. Indeed,experimental studies in acute myocardial infarction, renal ischemia,and hindlimb ischemia indicate that external application ofprogenitor cells is a suitable strategy to improve ischemiaand rescue organ function (13–17).
Various cell types have been approached to use to regeneratethe heart: skeletal myoblasts, cultivated after skeletal musclebiopsy (22–26), and bone marrow cells or circulating progenitorcells (27–29). Whereas skeletal myoblasts seem to be limitedto differentiate into cardiomyocytes, bone marrow or circulatingprogenitor cells may have a larger therapeutic potential, includingparacrine actions. Bone marrow cells have also been used inpatients with peripheral artery disease (Therapeutic Angiogenesisusing Cell Transplantation Study) (30). In addition, seriouslife-threatening ventricular arrhythmias have been observedin patients who received a cardiac application of skeletal myoblasts(22), which is not reported in patients who received bone marrow(27–30) or circulating progenitor cells (28).
Acute Myocardial Infarction
In a first clinical trial, Strauer et al. (29) treated 10 patientsafter an acute myocardial infarction by injecting progenitorcells that were aspirated from the bone marrow into the infarctcoronary artery. A positive effect on myocardial perfusion aswell as LV function was seen. Another pilot trial delivereda selected fraction of bone marrow cells (CD 133+ cells) tothe heart by intramuscular injection during surgery (32).
In the Transplantation of Progenitor Cells and RegenerationEnhancement in Acute Myocardial Infarction (TOPCARE-AMI) trial,finally 59 patients were investigated 3 to 7 d after successfulpercutaneous revascularization via stent implantation of aninfarct artery during acute myocardial infarction (27,28). Patientswere treated with either bone marrow–derived progenitorcells or circulating progenitor cells that were given duringlow-pressure balloon insufflation directly into the lumen ofthe infarct artery. The study demonstrated that intracoronaryinfusion of progenitor cells with both types of cells was safeand feasible, because there were no unexpected adverse eventsand no evidence of inflammation or microembolization inducedby the cell therapy. In addition, improvement of LV ejectionfraction was seen associated with improved viability measuredby positron emission tomography (27) and reduction of infarctsize, assessed by magnetic resonance imaging (late enhancement)(33). In addition, coronary flow reserve improved significantlyinto the infarct artery up to the level of the reference artery,giving a hint that probably neovascularization and, therefore,increases in vascular conductance capacity might be associatedwith progenitor cell therapy.
These encouraging results were confirmed by the recently presentedBone Marrow Transfer to Enhance ST-Elevation Infarct Regeneration(BOOST) trial (34), which randomized 60 patients 1:1 with acontrol group to intracoronary bone marrow–derived progenitorcell therapy after acute myocardial infarction. Whereas LV ejectionfraction improved by 6.7% in the bone marrow–treated group,there was only a marginal change of LV ejection fraction of0.7% in the control group, which demonstrated a significantdifference in favor of progenitor cell therapy. Further studieswill have to establish formally this novel therapy and definedefinitely the value within the current clinical scenario.
Chronic Ischemic Cardiomyopathy
In a chronic stage of ischemic heart disease, the prerequisitesfor a successful progenitor cell therapy are probably less favorablethan after an acute myocardial infarction. During acute myocardialinfarction, an acutely injured ischemic myocardium is sensitizedfor the reception of progenitor cells, because the endotheliumis activated, expresses receptors, and releases messenger moleculesthat target adherence and migration of progenitor cells.
To overcome the lack of an incentive of progenitor cells tomigrate to the chronically damaged heart, some studies havetried to inject bone marrow–derived progenitor cells directlyinto the heart muscle via percutaneous techniques or by surgery.Limited by usually a small patient number, these studies sofar indicate the safety and the feasibility of this kind oftreatment as well as give a hint toward efficiency, becausesome patients improved their ejection fraction (35–37).
A recent preliminary report of the MAGIC cell study (38) suggestedthat this kind of therapy might be associated with increasedrestenosis rate. However, because of various limitations ofthis study (incompletely reported small sample size, heterogeneouspatient population, delayed revascularization after acute infarction),the conclusions drawn from that study are limited. In contrast,other studies using progenitor cells alone (e.g., BOOST, TOPCARE-AMI)do not indicate an increased restenosis rate.
The use of stem or progenitor cells to treat or restore thefunction of damaged organs such as the heart or the kidney isa completely new therapeutic concept. In contrast to all previouslyexisting medical treatment strategies, progenitor cell therapydoes not only target to halt progression of the disease butfurthermore offers the perspective to actually regenerate thefunction. However, under discussion are various topics thathave to be resolved:
The mechanism of action of progenitorcells is not fully understood.It might include paracrine activityof the cells, neovascularization,and, probably, transdifferentiationor fusion. The relativeimportance of these various mechanismshas to be determined.In addition, other mechanisms that areyet unknown might beinvolved.
It might be necessary to optimizeprogenitor cell therapy, byenhancing mobilization and/or byenhancing homing of the cells.However, strategies that improvemobilization (e.g., granulocytecolony-stimulating factor) modifymolecular targets in a waythat mobilizes cells on the one handbut also impairs theirfunctional capacity to migrate and adhereon the other hand.Therefore, probably different strategieshave to be found.
The concept of cell therapy has to be morerefined. There iscurrently still no consensus on the combinationof cells orhow to identify the subtype of cells that givesthe best approachto reach the therapeutic goal. That is, themarkers used sofar to identify progenitor cells (e.g., CD34+or the more immaturemarker CD133+) are not linked directlyto the progenitor activityof the cell. In addition, therapeuticmethods to improve progenitorcell function (e.g., gene therapy)might be useful in the future.In addition, the best way toapply cells (number, route of application)has not yet beendefined.
Nevertheless, progenitor cell therapy gives new opportunitiesfor treatment of damaged organs. Clinical studies are currentlyongoing in patients with coronary artery disease, such as themulticenter, double-blind, controlled Reinfusion of EnrichedProgenitor Cells and Infarct Remodeling in Acute MyocardialInfarction trial comparing intracoronary infusion of bone marrowprogenitor cells versus placebo in 200 patients after myocardialinfarction. However, administration of progenitor cells hasnot been limited to actual application of cells; other strategiesmight involve enhancement of regenerative capacities of organ-specificresident progenitor cells (demonstrated in the heart, currentlyonly suspected in the kidney) by pharmaceutical strategies.Indeed, statins, which are known to improve cardiovascular prognosis,have been demonstrated to increase the number of circulatingprogenitor cells (38) and, of interest, increase the numberof circulating progenitor cells incorporated into the neointimaafter vascular damage, thereby counteracting the restenoticprocess (40,41).
There are also several potential fields of interest in nephrology,such as ischemic renal disease (17), regeneration of glomeruli,or tubular disease (42) or transplant vascular disease by modifyingreendothelialization with progenitor cells or reducing smoothmuscle proliferation and, thereby counteracting transplant vasculopathy(43).
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Top
Abstract
Introduction
-gal. Then, renal artery occlusion was performed to induce ischemia, which releases messenger stimuli to mobilize progenitor cells from the bone marrow. By staining for