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row stromal cells (MSCs)2. These cells werefirst discovered in the 1970s byFriedenstein, who showed that they are rel-atively easy to isolate from marrow by theiradherence to cell-culture surfaces, and thatthey differentiate both ex vivo and in vivointo osteoblasts, adipocytes, and chondro-cytes. MSCs fascinated a small group ofinvestigators following Friedenstein’s pio-neering work and began to attract widerattention in the mid-1980s, when they werefound to serve as feeder layers for thegrowth in culture of HSCs. In culture,MSCs promote the growth of HSCs notonly by secreting cytokines and other fac-tors but also by direct cell–cell contact,through a curious process in whichhematopoietic cells bury beneath MSCs forpart of their cycle of cell maturation.

Interest in MSCs was also stimulated bytheir potential role in tissue repair. For wellover a century, there has been speculation

A recent report by Verfaillie and colleagues1

demonstrates that a rare cell obtained fromhuman bone marrow has the remarkableability to serve as a precursor of bothhematopoietic cells and cells with charac-teristics of the visceral mesoderm, neu-roectoderm, and endoderm (Fig. 1). Thecharacterization of an adult stem cell capa-ble of giving rise to numerous cell types isan important step in elucidating the ori-gins of pluripotent cells in the body andultimately brings closer the promise ofstem cell therapies.

The observations of Verfaillie and col-leagues have been presaged by earlierreports—including some claiming to haveisolated a similar type of pluripotent stemcell—that either had to be withdrawn orfailed to convince the scientific communi-ty. In addition, a large number of recentreports on in vivo experiments have shownthat cells from bone marrow can provideprecursor cells for many tissues, includingbone, cartilage, skeletal muscles, liver,heart, epithelium, blood vessels, and thecentral nervous system2–9.

Research on adult stem cells has a curi-ous history. We have known for decadesthat cells in many tissues of adult animalshave short half-lives. The presence of astem cell that can divide to produce anexact copy of itself and a differentiateddaughter cell must therefore be essentialfor the survival of all the cellular elementsof the bloodstream and of tissues such asthe skin and the intestinal epithelium. Fora long time, such stem cells attracted littleattention, with the notable exception ofhematopoietic stem cells (HSCs)10. Interestin HSCs was driven by the ready accessibil-ity of the system and by the ease with whichfractions of cells from bone marrow couldbe used to rescue the hematopoietic sys-tems of mice and other animals whosemarrow had been ablated by chemotherapyor X-ray irradiation. Research on HSCs wasalso driven by the use of bone marrowtransplantation in patients, first as a thera-

py for lymphomas and more recently in thetreatment of acquired conditions such assevere forms of systemic lupus erythemato-sus and rheumatoid arthritis.

Although HSCs have inspired intensivestudy, interest in other adult stem cells haslagged far behind. Perhaps the best studiedof the other adult stem cells are anotherfraction of cells from bone marrow, vari-ously referred to as fibroblastoid colony-forming units, plastic adherent cells frommarrow, mesenchymal stem cells, or mar-

Adult stem cells gradually come of ageResearchers have identified an adult stem cell with anunprecedented capacity for differentiation.

Darwin J. Prockop

Figure 1. MAPCs derived from adult bone marrow isolated by Verfaillie and colleagues. The cells donot appear to senesce. They differentiate at the single-cell level into most somatic cells includinghematopoietic cells (the three germ layers are shown in boxes), acquire functional characteristics oftissues following differentiation in vitro, and engraft and differentiate into cells with tissue-specificmorphology in vivo. Figure adapted with permission from Verfaillie and colleagues1.

MAPCs

ES cells

Darwin J. Prockop is director of the Center forGene Therapy, Tulane University HealthSciences Center, New Orleans, LA 70112(dprocko@Tulane.edu).

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nature biotechnology • VOLUME 20 • AUGUST 2002 • http://biotech.nature.com

NEWS AND VIEWS

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that bone marrow may provide, in additionto inflammatory cells, progenitor cells thathome to sites of tissue damage and becomeboth the fibroblasts and tissue-specific cellsof tissue regeneration. This speculation hasbeen surprisingly difficult to prove defini-tively, but it has been supported by theremarkable ability of MSCs to differentiateinto many cell types.

More recently, initial studies showed thatMSCs or related cell elements from mar-row can engraft into many tissues afterinfusion into marrow-ablated or marrow-compromised rodents, including engraft-ment into the central nervous system2–4,8.Over the past several years, it has becomeincreasingly apparent that engraftment ofsuch cells is greatly enhanced by damage toa tissue. The cells promote tissue repaireither by proliferating and differentiatinginto the phenotype of the damaged cells orby creating a milieu that promotes regener-ation by endogenous cells of the tissue11–13.The role of MSCs or related cells in tissuerepair may account for the growing evi-dence that many tissues contain smallnumbers of cells with stem cell–like char-acteristics. Alternatively, many tissues mayhave independent systems of stem cells thatplay a role in regeneration.

The cells referred to as multipotent adultprogenitor cells (MAPCs) by Verfaillie andcolleagues are derived from cultures ofadherent cells from bone marrow. Thosethat initially appear in the cultures have thecharacteristics of MSCs. MAPCs becomeapparent only after the cells undergo 25 ormore population doublings and as a smallsubpopulation begins to replicate morerapidly. These MAPCs have a greaterpotential for differentiation than do MSCs,as they can differentiate into hematopoieticcells, whereas MSCs cannot. They thereforerepresent an earlier precursor cell, and assuch, have an intriguing biology. They mayalso have special advantages for use in thetherapy of some human diseases.

The work on adult stem cells byVerfaillie and colleagues and by manyother investigators has of course fannedthe political fires about research on humanembryonic stem (ES) cells. Unfortunately,the truth has been frequently obscuredboth by the political opponents of stem cellresearch and by overly enthusiastic scien-tists. In fact, we still do not fully under-stand any stem cell from any source. Muchof the basic biology of these cells remains amystery. For example, we can drive severalkinds of stem cells to differentiate in fasci-nating ways both ex vivo and in vivo, butwe do not know what molecular signalsconvert them from the process of self-replication to that of differentiation.

Until we understand such features of thecells, the extensive use of either embryonicor adult stem cells in patients represents agreat leap that should be undertaken onlyin patients with devastating terminal dis-eases. We must admit that the use of adultstem cells in patients still poses dauntingtechnological barriers. In particular, manyinvestigators and several biotech start-upcompanies are pursuing the strategy ofusing one or more universal donors to cre-ate a large stock of stem cells that can bethoroughly tested and then distributedmore or less at random to unrelatedpatients. This strategy faces two obviousbarriers. First, in differentiating, stem cellsfrom an unrelated donor will produce pro-teins that are foreign to the patient and aretherefore likely to provoke immune reac-tions. Second, to generate a large stock ofstem cells, one needs immortal cells thatcan replicate indefinitely. However,immortal cell lines are notorious for theirtendency to produce teratomas in animals,a step toward malignant transformation.Some stem cells such as ES cells consistent-ly generate teratomas; others such asMAPCs have not done so in preliminarytests.

Unfortunately, biological processes donot operate according to set thresholds forevents such as malignant transformationsor lethal side effects of drugs. Biologicalresearch is limited to determining theprobabilities of such unfortunate events,and in the end many of these are not seenuntil trials are carried out in thousands ofpatients. At the same time, the currententhusiasm about both embryonic andadult stem cell research is well placed.Some theories will have to be corrected aswe learn more about the cells using newtechnologies such as microarrays for bothmRNAs and proteins. And much remainsto be learned about potential clinical appli-cations. But the possibility of curing nowincurable diseases that affect millions ofindividuals is clearly on the horizon.

1. Jiang, Y. et al. Nature 418, 41–49 (2002).2. Prockop, D.J. et al. Science 276, 71–74 (1997).3. Pereira, R.F. et al. Proc. Natl. Acad. Sci. USA 95,

1142–1147 (1998).4. Ferrari, G. et al. Science 279, 528–530 (1998).5. Orlic, D. et al. Nature 410, 701–705 (2001).6. Petersen, B.E. et al. Science 284, 1168-1170

(1999).7. Krause, D.S. et al. Cell 105, 369–377 (2001).8. Kopen, G., Prockop, D. & Phinney, D. Proc. Natl.

Acad. Sci. USA 96, 10711–10716 (1999).9. Mezey, E., Chandross, K.J., Harata, G., Maki, R.A. &

McKercher, S.R. Science 290, 1779–1782 (2000).10. Weissman, I.L. Science 287, 1442–1446 (2000).11. Chopp, M. et al. Neuroreport 11, 3001–3005

(2000).12. Kotton, D.N. et al. Development 128, 5181–5188

(2001).13. Hofstetter, C.P. et al. Proc. Natl. Acad. Sci. USA 99,

2199–2204 (2002).

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