355Clinical Science (2002)
103
, 355–369 (Printed in Great Britain)
R E V I E W
Adult stem cell plasticity: new pathways of tissue regeneration become visible
Stuart J. FORBES
*
†, Pamela VIG
*
†, Richard POULSOM
*
, Nicholas A. WRIGHT
*
and Malcolm R. ALISON
*
‡
*
Histopathology Unit, Cancer Research UK, London, U.K., †Department of Medicine, Faculty of Medicine, Imperial College of Science, Technology and Medicine (ICSTM), St Mary’s Hospital, London, U.K., and ‡Department of Histopathology, ICSTM,Hammersmith Hospital, London, U.K.
A B S T R A C T
There has recently been a significant change in the way we think about organ regeneration. Inthe adult, organ formation and regeneration was thought to occur through the action of organ-or tissue-restricted stem cells (i.e. haematopoietic stem cells making blood; gut stem cellsmaking gut, etc.). However, there is a large body of recent work that has extended this model.Thanks to lineage tracking techniques, we now believe that stem cells from one organ system,for example the haematopoietic compartment, can develop into the differentiated cells withinanotherorgansystem,suchasliver,brainorkidney.Thiscellularplasticitynotonlyoccursunderexperimental conditions, but has also been shown to take place in humans following bonemarrow and organ transplants. This trafficking is potentially bi-directional, and even differen-tiated cells from different organ systems can interchange, with pancreatic cells able to formhepatocytes, for example. In this review we will detail some of these findings and attempt toexplain their biological significance.
INTRODUCTION
Each organ and tissue is perceived to possess a subpopu-lation of cells capable of self-maintenance, indefiniteproliferativepotentialandtheabilitytogiverisetoalargefamily of descendants, i.e. to be clonogenic. These stemcells usually give rise to a limited number of different celllineages within their normal environs, such multipoten-tiality being a feature of tissue- and organ-specific stemcells [1]. This review focuses on a hitherto unsuspectedproperty of tissue-specific stem cells, i.e. the ability togive rise to cell types in a new location, that are notnormally present in the organ in which the stem cells arelocated – a property we refer to as stem cell plasticity.The stem cells that are thought to be most flexible comefrom the inner cell mass of the blastocyst: these cells are
Key words:
bone marrow stem cells, lineage tracking, plasticity, transdifferentiation, transplants.
Abbreviations:
CNS, centralnervoussystem;ES cells,embryonic stem cells;FAH,fumarylacetoacetatehydrolase;FGF, fibroblastgrowthfactor;G-CSF,granulocytecolony-stimulatingfactor;GFAP,glialfibrillary acidicprotein;GFP,greenfluorescent protein;eGFP, enhanced GFP; HSC, haematopoietic stem cell; MSC, mesenchymal stem cell; OI, osteogenesis imperfecta; NOD,non-obese diabetic; SCID, severe combined immunodeficient; SDF, stroma-derived factor; SP cells, side-population cells.
Correspondence:
Dr S. J. Forbes, Hepatology Section, Division of Medicine, Faculty of Medicine, Imperial College London, 10thfloor QEQM Wing, South Wharf Road, London W2 1NY, U.K. (e-mail s.j.forbes
!
ic.ac.uk).
essentially pluripotential, being capable of giving rise tocells found in all three germ layers. However, the ethicalissues surrounding the use of embryonic stem cells (EScells) from early human embryos have caused concern.There may, however, be alternatives to the use of EScells, as certain adult stem cells appear to be more flexiblethan previously thought. Numerous papers have chal-lenged the long-held belief that organ-specific stem cellsare lineage-restricted. In particular, haematopoietic andneural stem cells appear to be the most versatile at cuttingacross lineage boundaries (see Table 1). Of course, it isone thing for a circulating cell to engraft in another organand assume some or all of the phenotypic traits of that organ; this is known as transdifferentiation – theacquisition of a new phenotype. It is quite another toclaim that the engrafted cell is a stem cell for its new
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2002 The Biochemical Society and the Medical Research Society
356 S. J. Forbes and others
Table1 Examples of adult stem cell plasticity, basedon lineage tracking and phenotype determination
Abbreviations: ISH,
in situ
hybridization for Y chromosome; CK, cytokeratin; G-6-Pase, glucose-6-phosphatase;
β
-Gal,
β
-galactosidase.Donor cells Recipient organ Cell type Proof of donor origin/proof of new phenotype ReferencesBone marrow Liver Oval cells, hepatocytes (rat) ISH and MHC class II antigen L21-6/morphology [74]KTLS cells Liver Hepatocytes (mouse)
β
-Gal/FAH
+
[6]Bone marrow Liver Hepatocyes (human) ISH/CK8 and albumin [76,77]Pancreatic exocrine cells Liver Hepatocyte (mouse) GFP/G-6-Pase and transferrin [87]Pancreas Liver Hepatocyte (mouse) ISH/FAH
+
[88]Bone marrow Liver Endothelium (mouse, human) ISH/factor VIII [54]Bone marrow Kidney Tubular epithelium glomeruli (mouse, human) ISH/cytochrome P450 and CAM 5.2 [47]Bone marrow Kidney Endothelium (human) XX chromosome and HLA typing/morphology [46]Extra-renal Kidney Endothelium (human) Barr-body detection/morphology [44]Bone marrow Heart Myocardium (mouse) ISH and GFP/cardiac myosin [31]Bone marrow SP cells Heart Cardiomyocytes and endothelium (mouse)
β
-Gal/cardiomyocytes:
α
-actinin and endothelial cells: Flt-1 [58]Bone marrow Lung Type 1 pneumocytes (mouse) ISH/surfactant B [65]Neuronal Marrow Multiple haematopoietic lineages (mouse)
β
-Gal/morphology [103]Bone marrow CNS Neurons ISH/NeuN [107]Bone marrow CNS Microglia and astrocytes ISH and GFP/macrophage antigen F4/80 [108]
found home. Ideally this would require the isolation andtransplantationofsinglecellsthatself-renewandproducea large family of descendants (clonogenicity) that eventu-ally become fully functional; these robust criteria havebeenmetinoneortwocases.However,somecommenta-tors have added that this phenomenon should be ob-served to occur ‘naturally’ in organs not forced toundergo organ degeneration before accepting that stemcells jump lineage boundaries [2]. Although this doesoccur to a limited extent, we will argue that it is preciselybecause of severe organ damage that transdifferentiationoccurs more readily, and that the likes of haematopoieticstem cells (HSCs) can act as a back-up system when anorgan’s own regenerative capacity is overwhelmed. Thusthe lack of transdifferentiation in the absence of organdamage in no way invalidates the claim that it does occur,and it is largely in the clinical context of severe organdamagethatwewouldenvisageexploitingtheuseofstemcells with transdifferentiating potential. We will alsobriefly review the evidence that some adult stem cellsmay even be pluripotential, albeit in the context of creating chimaeric animals, for example in the abilityof adult HSCs to contribute to all three germ layersin the pre-immune foetal sheep and the NOD
\
SCID(non-obese diabetic
\
severe combined immunodeficient)mouse after injection into the blastocyst.
STEM CELL PLASTICITY:TRANSDIFFERENTIATION OR FUSION?
Regenerative medicine is big news in both the biomedicaland the popular press, and there has been a vigorousdebate regarding the therapeutic potential of ES cellsversus adult stem cells. Recently, doubt has been castupon the claims that certain adult stem cells, particularlyfrom the bone marrow and central nervous system(CNS), can jump lineage boundaries to generate com-pletelynewtypesofcells.Theevidenceforadultstemcellplasticity often relies on the appearance of Y chromo-some-positivecellsinafemalerecipientofabonemarrowtransplant from a male donor. Alternatively, markerssuch as LacZ or green fluorescent protein (GFP) havebeen used (see Figure 1), and these techniques are usuallycombined with lineage markers in an attempt to show aswitch in the fate (transdifferentiation) of the trans-planted cells. However, two publications have suggestedthat these phenomena could be due to the fusion of bonemarrow cells with the differentiated cells in the neworgan. When bone marrow from GFP transgenic micewas mixed with ES cells, a very small proportion (2–11hybridclones
\
10
'
marrowcells)ofthebonemarrowcellsfused with ES cells, and these cells could subsequentlyadopt some of the phenotypes typical of ES cell dif-ferentiation [3]. A very low frequency of fusion (oneevent
\
100000 CNS cells) was reported when mouseCNS cells were mixed with ES cells, and here the derivedhybrid cells were able to show multilineage potentialwhen injected into blastocysts, most prominently intoliver [4]. While these observations do raise the possibilitythatthe apparent transdifferentiationevents are the resultof cell fusion (so-called heterokaryons), this speculationis at odds with a number of observations. For example, arecent report suggested that post-partum thyroiditis maybe due to transplacentally acquired foetal cells causing analloimmune disease (previously regarded as an autoim-mune disease) [5]. In this report, one female patient hadclusters of fully differentiated thyroid follicular cellsbearing one X and one Y chromosome; of course, thesource of the transdifferentiated cells was the foetus
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2002 The Biochemical Society and the Medical Research Society
357Adult stem cell plasticity
Figure 1 Methods commonly used to track the fate of transplanted bone marrow
rather than a deliberate transplant, but nevertheless nofollicular cells were XXXY, suggesting that cell fusionwas not responsible for the phenomenon.Furthermore, in mice, the ability of bone marrow cellsto cure a metabolic liver disease has been established [6].Female mice deficient in the enzyme fumarylacetoacetatehydrolase (FAH
−/−
, a model of fatal hereditary tyrosi-naemia type 1), can be biochemically rescued by 10
'
unfractionated bone marrow cells that are wild type forFAH. Moreover, as few as 50 HSCs were capable of biochemical rescue. The very low levels of fusionreported with ES cells also makes it unlikely that suchhybrids could be responsible for the multi-focal livercolonization by ‘marrow-derived’ hepatocytes seen inthis model. On the other hand, if fusion was responsible,then clearly these hybrids had a selective growth ad-vantage, turning unhealthy hepatocytes into metaboli-cally competent hepatocytes, and would not negate thetherapeutic potential of bone marrow cells in the liver.Moreover, bone marrow stem cells are common in cordblood and are even found in peripheral blood: if widespread fusion exists, we would all have large num-bers of polyploid cells in many organs. This has not beenreported outside the liver, where polyploidization doesoccur on a large scale, due to binucleate cells segregatingonthesamemitoticspindle.Untilexperimentsarecarriedout that show heterokaryon formation when adult stemcells‘transdifferentiate’
invivo
,thenextrapolationsfromrare events involving ES cells are premature.
BONE MARROW
Adult bone marrow contains HSCs and mesenchymalstem cells (MSCs), both of which may derive from acommon primitive blast-like cell precursor able todifferentiate along MSC or HSC potentials [7].
HSCs
The hierarchy of human haematolymphopoietic cells isdefined by functional assays. HSCs with extensive self-renewal capacity are assayed
in vivo
for their capacity toxenograft immunodeficient NOD
\
SCID mice and pre-immune sheep foetuses. These models are surrogates forasyngeneictransplantationassay.Primitivehaematolym-phopoietic cells with limited self-renewal potential areidentified
in vitro
as high-proliferative-potential colony-forming cells. Lineage-committed haematolymphopoi-etic cells with no self-renewal activity are also defined
invitro
by clonogenic assays as colony-forming units orburst-forming units.Within the bone marrow, HSCs reside in niches thatsupport all the requisite factors and adhesive properties
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2002 The Biochemical Society and the Medical Research Society
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