Identityofthe ‘transdifferentiating’stemcells Whatcelltypesinthedonorpopulationarethesourceof the ‘converted’cells? In manystudies, researchers used crude mixturesofdonorcellsratherthanisolatedorgan-specificstemcells. Itisthereforenotclear whetherthecells thatgeneratetheheterologouscelltypearereallytheorganspecificstemcellsofthedonortissue, orsomeothercell type, perhapsevenanerrantstemcellfromthehosttissue.(Forexample, HSCarepresentinandrapidlyfluxthrough bloodto other, non-hematopoietictissuesinlarge numbers.) Untiltheconversionphenomenonisshowntooccur usingisolatedstemcellsfromthedonortissueofinterest, it willremainuncertainwhetherstemcellsfromagivenorgan canactually ‘jumpthelineagebarrier’andgeneratedifferentiatedderivativesofanotherorgan. Insomepublications, forexample, bloodtransplantsofbone marrow, mobilized bloodorumbilicalcordareerroneouslylabeledas HSCor stemcelltransplants. Inthecaseof ‘bloodinto muscle’11, theidentityoftheresponsible marrowcellsremainedin somedoubtuntilapopulationof marrowcellshighlyenrichedforblood-formingstemcells wasalsoshowntocontain such myogenic precursors13. Another study convincinglyshowsthat prospectivelyisolated HSCscan differentiatetolivercellsinvivo, andthattheregenerated liversarefunctional14. culturedstemcells maydifferentiateinvitro Evenifisolatedstemcellshavebeenusedasdonor material, havetheybeenculturedpriortotransplantation? Forexample, untilrecently7 neuralstemcellshavebeenisolatedby growthinvitro, ratherthanbyprospectivepurificationfrom unculturedtissueasperformedfor HSCs. Inseveralstudies, suchculturedneuralstemcellshavebeenshowntotransdifferentiateintoblood11, muscle15 oravarietyofothernonneuro-ectodermalderivatives16. Thepriorexposureofsuch cellstoacultureenvironmentraisesthequestionofwhether theplasticitytheyexhibitisreallyapropertytheypossessin vivo, orifitisacquiredinvitro. Givenrecentexamplesofreprogramminginvitro17–20, this possibility hastobetaken moreseriously. Ifthepropertiesofthecells haveindeed beenalteredbythe manipulationsnecessarytoisolatethem, thisleavesopenthepossibilitythattheycouldexhibitunpredictablebehaviorsifusedinatherapeuticcontext.