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Journal of the American College of Cardiology Vol. 55, No. 20, 2010© 2010 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00Published by Elsevier Inc. doi:10.1016/j.jacc.2009.12.050

EDITORIAL COMMENT

egenerative Medicinedvancing Health Care 2020*

ndre Terzic, MD, PHD,imothy J. Nelson, MD, PHD

ochester, Minnesota

egenerative medicine has begun to define a new perspec-ive of future clinical practice. The U.S. Department of

ealth and Human Services report “2020: A New Vision—Future for Regenerative Medicine” highlights that regen-

rative medicine is the vanguard of 21st-century health care1). Patients and society increasingly expect that regenera-ive medicine will lead to repair of diseased organs, injuredissues, or congenital anomalies. From pioneering successith bone marrow transplants for select hematologicalisorders that are now standard of care (2) to the mostecent advances in bioengineered stem cell platforms thatrovide unlimited sources of autologous pluripotent progen-tors and broaden the scope of individualized diagnosis andherapy (3), National Institutes of Health and Nationalcademies recognize regenerative medicine as a most prom-

sing core component of modern medical practice (4,5).

See pages 2232 and 2244

ithout the contribution of personalized products andervices emerging from regenerative medicine technology,xperts caution that health care will face an escalation innefficient treatments and a rising global cost (6). Aimedoward functional restoration of damaged tissues, not a merebatement or moderation of symptoms, regenerative medi-ine offers a “disruptive innovation” strategy uniquely poisedo add value and transform health care by providing tailored,urative solutions for the unmet needs of our patients (7,8).

Tissue repair might provide a sustained therapeutic ad-antage in a spectrum of conditions ranging from congenitaliseases to acquired, age-related pathologies. Applied in theanagement of cardiovascular diseases, the rapidly devel-

ping regenerative medicine armamentarium promises sig-ificant human health benefit with tangible outcomes for

ncreased quality of life and improved patient care, building

Editorials published in the Journal of the American College of Cardiology reflect theiews of the authors and do not necessarily represent the views of JACC or themerican College of Cardiology.From the Marriott Heart Disease Research Program, Division of Cardiovascular

iseases, Departments of Medicine, Molecular Pharmacology, and Experimentalherapeutics, and Medical Genetics, Mayo Clinic, Rochester, Minnesota.

n breakthroughs in stem cell biology paired with successesn transplant medicine. Maximizing potential return, how-ver, mandates an integrated roadmap across the transla-ional continuum of discovery-development-regulation-use9) to ensure optimal application of regenerative medicinelgorithms in practice.he “R3” paradigm of repair. The framework for heart

epair relies on the general principles of “rejuvenation↔eplacement↔regeneration” (Fig. 1). The “R3” paradigm ofherapeutic repair underscores the complementary strategieshat conceptualize the scope of regenerative medicine (8).rom heart muscle self-renewal (“rejuvenation”) to

ransplantation-based organ recycling (“replacement”) and,ltimately, biogenesis of new tissue parts for de novo tissueestoration (“regeneration”), the core components of theepair triad offer natural or engineered means to ensureissue homeostasis and achieve sustainable cure (Fig. 1).

Fundamental to the innate processes of cardiac tissueejuvenation is cardiomyocyte renewal, characterized by thengoing recruitment of resident progenitor pools within orutside the heart (10,11). Self-repair mechanisms continu-usly contribute to tissue homeostasis (12), although theirfficacy is variable among individuals and is compromised byatient age, disease status, comorbidities, concomitantharmacotherapy, as well as genetic, epigenetic, or ecoge-etic influences. Radioisotope decay in the human body, aemnant of nuclear bomb testing half-a-century ago, hasecently offered an unprecedented opportunity to quantifyhe birth date of single cardiomyocytes, indicating thatne-half of the heart mass can be potentially renewed overlifespan (13). Notably, stem cell contribution to postnatal

Figure 1 The “R3” Paradigm of Heart Repair

The “R3” triad of rejuvenation, replacement, and regeneration encompassesprocesses underlying human heart repair. Rejuvenation refers to self-repairthrough innate mechanisms of cardiomyocyte renewal, maintaining tissuehomeostasis. Replacement refers to transplantation of recycled parts for organsubstitution. Regeneration refers to engraftment and differentiation of progeni-tor cells to restore tissue function through cell-based repair.

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2255JACC Vol. 55, No. 20, 2010 Terzic and NelsonMay 18, 2010:2254–7 Regenerative Medicine

eart formation has been validated by the self/non-selfhimerism characteristic of patients after allogeneic trans-lantation (14). Furthermore, stem cell loads increase inailing hearts, involving derivation of cardiomyocytes fromirculating as well as resident progenitor pools (15,16).ejuvenation revitalizes the innate cardioprotective poten-

ial, yet in the context of large-scale destruction—as is thease after massive infarction—inherent repair mechanismsre typically inadequate to salvage a deteriorating myocar-ium (17).Likewise, transplant medicine exploits a replacement

trategy as a valuable option to recycle used parts and restoreailing organ function by means of exogenous substitutes—t is limited, however, by donor shortage. There are anstimated 2,500 heart transplants performed annually in the.S.; yet over 100,000 additional patients would benefit

rom this lifesaving procedure in this country alone (18).ue to the magnitude of such growing clinical need,

lternative strategies, including mechanical assist devices,re increasingly explored. From the initial intent of “bridg-ng” to transplant or recovery, success of this technology hased to newer indications, including permanent or “destina-ion” therapy in selected patients. However, these significantdvancements do not prevent the increasing pandemic ofefractory heart failure, currently managed by treatments toimit symptomatic progression of incurable disease.

A boost in healing processes would stimulate the adaptiveesponse and promote adequate biogenesis of functionalissue to abrogate the progression of heart disease. Extrap-lating from the paradigms of natural heart rejuvenationnd transplant-based organ replacement, reactivation ofndogenous and/or introduction of exogenous progenitorells into the injured heart would thereby offer a legitimatearget to ameliorate the burden of disease. In this regard,tem cell-based regeneration has revealed the next frontierf medical therapy aimed at achieving structural and/orunctional repair (19–21). The regenerative strategy referso engraftment of progenitor cells that requires in vivorowth and differentiation to establish a repair outcomeithin the host environment. Collectively, approaches for

tem cell-based regenerative medicine are poised to drivehe evolution of medical sciences from traditional palliationoward curative therapy by supplementing resident progen-tor pools and facilitating chimeric healing of damagedissues.tem cell-based regeneration. Classified as “biologics,”tem cells are a distinct class of medications produced byeans of biological processes (22,23). In contrast to tradi-

ional pharmaceuticals, regenerative cytotherapy productsontain viable cells as the active ingredient (24). Worldwide,ver 3,000 patients with ischemic heart disease have re-eived stem cell therapy in a clinical trial setting. Meta-nalyses underscore feasibility and safety of stem cell-basedherapy and point to modest albeit variable improvement inunctional parameters of recovery (25). These initial trials

ely on the use of first-generation products consisting of d

urified, natural human cells, typically in their native state,uch as naïve mesenchymal stem cells isolated from theatient’s bone marrow (20,26). Ongoing optimization anddentification of the most appropriate cell source and cellype, means to enhance safety and effectiveness, selection ofatient populations most amenable to cell-based therapy,deal timing of intervention, and most favorable route ofdministration are among the areas of focus to determinehe clinical scope and maximize benefit of cell-based therapyn the management of cardiovascular disease (26–28).

Indeed, beyond initial concerns of feasibility and safety,stablishing the functional and structural efficacy profiles ofpecific stem cell-based treatments is paramount to foster aonscious application in future practice (28). It should beoted that most clinical studies to date have tested hetero-eneous cell populations associated with mixed results25–28).

Head-to-head comparisons between stem cell platforms,s exemplified in this issue of the Journal with the carefulharacterization of distinct adult progenitor populations29,30), are critical in directing the selection of the mostaluable stem cell cytotypes and guiding the rational designf next-generation clinical trials. These prototypic, well-esigned studies rely on blinded, randomized, clinicallyelevant approaches, and use high stringency parameters ofifferentiation potential and repair outcome (29,30). Spe-ifically, Armiñan et al. (29) report that intramyocardialransplantation of human mesenchymal stem cells andD34� hematopoietic cell progenitors—isolated from bonearrow and umbilical cord blood, respectively—improve left

entricular function and increase cell proliferation and neoan-iogenesis in healing infarcted myocardium. At equipotentose with regard to benefit on fractional shortening, mesen-hymal stem cells were found superior in reducing infarct sizend preventing ventricular remodeling in this nude rodentisease model (29). The propensity of mesenchymal stem cellso migrate from the site of injection to the infarcted zonend their additional aptitude to reduce collagen depositionere suggested contributors to favorable outcome (29).ubois et al. (30), with selected porcine progenitor popu-

ations delivered by intracoronary infusion in a large animalodel of acute myocardial infarction, report that autologous

ate-outgrowth endothelial progenitor cells are particularlyffective in improving myocardial remodeling favoringreater vascular density than naïve allogeneic mesenchymaltem cell counterparts. Pro-angiogenic and paracrineatrix-modulating effects were inferred on the basis of the

ene expression and protein release profiles of culturedrogenitor cell populations, consistent with a greater neo-ascularization potential of autologous late-outgrowth en-othelial progenitor cells capable of secreting placentalrowth factor, a member of the vascular endothelial growthactor family, and a key molecule in angiogenesis andasculogenesis (30). The authors indicate that modes of

elivery, immunological status, and cardiomyogenic pre-

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2256 Terzic and Nelson JACC Vol. 55, No. 20, 2010Regenerative Medicine May 18, 2010:2254–7

pecification are all critical in influencing long-term out-ome (30).

Together these studies underscore the necessity for con-inuous advancements in discovery science to increase thenderstanding of stem cell biology in the context of theecipient diseased environment and the mechanisms ofyocardial repair. The nature of autologous versus alloge-

eic stem cell sources, the degree of cardiomyogenic versusasculogenic potential, and the severity of disease-affectedegments are all critical variables raised by these studies thateed consideration for a more efficient translation fromroof-of-concept studies to targeted application (29,30). Inact, it is anticipated that an increasing number of compar-tive studies will be the focus topic of imminent basic andlinical studies in cardiovascular regenerative medicine.ltimately, the rigor of comparative effectiveness outcome

nalysis with the potential to inform practice, improve care,nd influence costs (31) applied across regenerative plat-orms as well as between stem cell-based therapies andurrent medical/surgical state-of-the-art management op-ions will provide the cornerstone of future evidence-basedtandard of care and define reimbursement policy.linical development. At this stage of product develop-ent, proper pharmacodynamic and pharmacokinetic cer-

ifications are mandatory steps (21,22). Suitable markers ofiological activity are needed to adequately identify primaryharmacodymanic properties, even if the mechanism(s) ofction remain only partially understood. In addition, estab-ishing the optimal amounts and formulation of safe cell-ased medicinal products needed to achieve the desiredffects is a critical component of proving overall efficacy andpplicability. Pharmacokinetic considerations include pa-ameters of cell biodistribution, cell viability, and cellroliferation following single- or multiple-dose regimens.ngoing clinical studies are increasingly designed to pro-

ide an adequate demonstration of efficacy in the targetatient population, demonstrate an appropriate dose sched-le for optimal therapeutic effect, and/or evaluate theuration of therapeutic effect for risk-benefit assessment26). Accordingly, clinical safety databases are developed tonnotate adverse events, including procedural risk, immuneesponse, infection, malignant transformation, and long-erm safety. Continuous rigor in product development wille particularly needed as novel cell types, autologous orllogeneic, naive or lineage-prespecified, natural or bioengi-eered, are considered for human testing in the upcomingecade (21,32–34).Cell-based medicinal products involve cell samples of

imited amounts, mostly to be used in a patient-specificanner. This raises issues pertaining to quality-control

esting designed for each product under examination.herefore the manufacture of cell-based medicinal productsust be carefully designed and validated to ensure product

onsistency and traceability. Control and management ofanufacturing and quality-control testing are carried out

ccording to Good Manufacturing Practice requirements

24). Screening for purity, potency, infectious contamina-ion, and karyotype stability have become necessary ele-ents (i.e., release criteria), in compliance with standard

perating practices for production and banking of cells useds autologous or “off-the-shelf” allogeneic therapy. Accord-ngly, the U.S. Food and Drug Administration and theuropean Medicines Agency impose regulatory guidelines

or risk assessment, quality of manufacturing, preclinical andlinical development, and post-marketing surveillance oftem cell biologics for translation from bench to bedside toopulations (22,23).ndividualized applications. Individualized medicine pro-ides a powerful engine to tailor molecular profiles ofatients to maximize therapeutic specificity, reduce treat-ent variability, and minimize adverse events (35). Insights

n the regenerative basis of cell, tissue, and organ functionnd their interface with the environment will increasinglyefine disease risk, identify processes mediating diseaseusceptibility, or target mechanism-based therapies, therebyroviding previously unanticipated opportunities foratient-specific disease management. The emerging field ofegenerative medicine will thus grow in conjuncture withhe realization of the individualized medicine paradigm toreate predictive, personalized, and preemptive solutions forailored patient-specific strategies. Individualized treatmentlgorithms for regenerative medicine will require quantifi-ation of the inherent reparative potential to identify pa-ients who would benefit from stem cell therapy (24). In thisontext, the “stem cell load” specific to each patient willerve as an “index for regenerative potential” that will proveseful for prediction, diagnosis, prognosis, and targeting ofafe and effective therapies at the earliest stage of disease inhe new era of individualized regenerative medicine.

eprint requests and correspondence: Dr. Andre Terzic, Mayolinic, Siebens 5, 200 First Street Southwest, Rochester, Minne-

ota 55905. E-mail: terzic.andre@mayo.edu.

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ey Words: clinical translation y comparative effectiveness y heartepair y individualized medicine y regeneration y rejuvenation y

eplacement y stem cells y transplantation.