Concise Review: Stem Cell Antigen-1: Expression, Function, and Enigma - 《stemcells》干细胞学杂志干细胞之家



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发表于 2009-3-5 00:54 |只看该作者 |倒序浏览 |打印

作者：Christina Holmesa, William L. Stanforda,b作者单位：aInstitute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada;bDepartment of Chemical Engineering and Applied Chemistry, Institute of Medical Science, University of Toronto, Toronto, Canada
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      【摘要】$ i; x7 N; ^+ Y- M$ m
   Cloned 20 years ago, stem cell antigen-1 (Sca-1) is used extensively to enrich for murine hematopoietic stem cells. The realization that many different stem cell types share conserved biochemical pathways has led to a flood of recent research using Sca-1 as a candidate marker in the search for tissue-resident and cancer stem cells. Although surprisingly little is still known about its biochemical function, the generation and analysis of knockout mice has begun to shed light on the functions of Sca-1 in stem and progenitor cells, demonstrating that it is more than a convenient marker for stem cell biologists. This review summarizes the plethora of recent findings utilizing Sca-1 as a parenchymal stem cell marker and detailing its functional role in stem and progenitor cells and also attempts to explain the lingering mysteries surrounding its biochemical function and human ortholog.) J$ |, _5 k4 \, ?! Y) x# V+ i

Disclosure of potential conflicts of interest is found at the end of this article. 9 f9 a  ?0 n& m+ s9 z
      【关键词】 Stem cell antigen- Lymphocyte activation protein-A Stem cell Self-renewal Glycosyl phosphatidylinositol-anchored protein Lipid rafts
   INTRODUCTION
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Stem cell antigen-1 (Sca-1) is an 18-kDa mouse glycosyl phosphatidylinositol-anchored cell surface protein (GPI-AP) of the Ly6 gene family. Originally identified as an antigen upregulated on activated lymphocytes more than 30 years ago . Like other GPI-APs, Ly6 proteins are thus physically located in an ideal position from which to regulate or coactivate cell signaling via receptor-ligand binding or other protein-protein interactions; however, the exact molecular mechanism by which these proteins act remains unclear.
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EXPRESSION" P  y6 L# T% h
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Sca-1 is the most common marker used to enrich adult murine hematopoietic stem cells (HSCs) .
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Sca-1 expression is regulated in a complex fashion in hematopoietic ontology. As HSCs differentiate into common myeloid progenitors, Sca-1 expression is downregulated .

Outside the hematopoietic system, Sca-1 is similarly expressed by a mixture of stem, progenitor, and differentiated cell types in a wide variety of tissues and organs. Thus, Sca-1 is used routinely in combination with negative selection against mature markers for enrichment of stem and progenitor cells. With the exception of flow cytometry (fluorescence-activated cell sorting), traditional methods for detecting this Sca-1 expression have posed many challenges. Redundancy among Ly6 genes prevents Northern analysis from being useful and requires exceptionally stringent reverse transcription- or quantitative-polymerase chain reaction conditions, whereas various Sca-1 antibodies are less than ideal for Western analysis and immunostaining. Transgenic mouse lines using a Sca-1 promoter driving LacZ  have thus proved instrumental in facilitating more detailed expression studies. Overall, Sca-1 is expressed in the hematopoietic system, bone marrow, kidney, uterus, brain, mammary gland, prostate, liver, lung, pancreas, skin, thymus, lymph nodes, spleen, muscle, and bone of adult mice as well as the aorta-gonad-mesonephros, yolk sack, limb buds, urogenital ridge, liver, and hindgut region of midgestation embryos.' o* A# X2 E- d, n( X
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Sca-1 Expression Associated with Tissue-Resident Stem and Progenitor Cells

Using strategies based upon HSC enrichment, many groups are attempting to prospectively isolate and characterize stem/progenitor cells from a variety of tissues. To date, Sca-1 expression has been identified on putative stem/progenitor cell populations within the skeletal system . However, whether these Sca-1 positive populations are truly tissue-specific precursor/stem cells or represent hematopoietic, mesenchymal, or endothelial precursor/stem cells associated with these tissues is not known in all cases. Intriguingly, Sca-1 is also upregulated in a variety of murine tumors, consistent with the cancer stem cell theory.: f  @% Q: Z: H- }
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Often, Sca-1 is coexpressed with side population (SP) activity, another phenotypic marker used to enrich stem/progenitor cells. SP cells efflux Hoechst dye via the ATP-binding cassette transporter protein ABCG2, thus appearing on the side of the FACS bulk population. Like Sca-1 expression, SP activity enriches for HSCs . Although unlikely to be universal stem/progenitor cell markers, Sca-1 expression and/or SP activity are often used as candidate markers to fractionate cell populations to test for stem/progenitor cell characteristics. However, marker expression without accompanying functional assays, such as clonal multipotentiality and self-renewal, is largely meaningless. Additionally, in situ localization analysis of marker expression within the tissue is crucial to distinguish between tissue-specific resident stem/progenitor cells and multipotent hematopoietic, endothelial, or mesenchymal progenitors associated with the tissue vasculature and circulation, all of which express Sca-1.
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Although Sca-1 is widely used to prospectively isolate stem cells from various tissues, in many systems robust in vitro and in vivo functional stem cell assays have yet to be developed, making it difficult to discern between bona fide stem cells and their committed progeny (i.e., those with a lower capacity for self-renewal and higher probability of undergoing terminal differentiation). Furthermore, controversies remain as to the nature, function, and/or origin of the prospective stem/progenitor populations isolated from certain tissues using presently available methods. The following is thus intended to summarize the available evidence, given current state of the art techniques, linking Sca-1 expression with stem/progenitor cell activity (Table 1) and cancer." }0 u6 N6 s, u, s6 D; R9 U

Table 1. Stem/progenitor cell characteristics reported for tissue-resident Sca-1  cell populations3 K8 ^* }0 a3 w/ P2 |( u( W- Q; G

Musculoskeletal System

Adherent marrow-derived mesenchymal stem cells/mesenchymal progenitor cells (MSC/MPC), although largely heterogeneous, express Sca-1 together with the adhesion molecules CD29 and CD44 and show no expression of hematopoietic and endothelial markers such as CD45, CD11b, and CD31. Subpopulations of these progenitors have been demonstrated to differentiate both in vitro and in vivo into lineages including bone, fat, cartilage, and muscle and have contributed to in vivo repair of bone and cartilage defects .: ?2 M  M. |/ S$ L) f  s' ]7 Y

Although it remains controversial whether skeletal muscle satellite (stem) cells express Sca-1 . Whether this population of Sca-1-expressing nonhematopoietic cells is distinct from bone marrow-derived MSC remains to be elucidated." o. c& @4 e2 K7 r5 a0 N% p/ |

Prostate9 A3 b$ }( C! ?# c# a3 M" Y! H
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FACS analysis of dissociated murine prostate tissue revealed Sca-1 expression in 15% of cells . Thus, Sca-1 can be used to enrich for murine prostate cells that display many stem/progenitor cell-like properties.
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Dermis7 ?+ F- b- r+ a5 ~6 g

The neonatal and adult dermis contains neural crest-derived multipotent cells called skin-derived precursors (SKPs). SKPs express Sca-1, nestin, and fibronectin and can differentiate in vitro into mesodermal cells (smooth muscle and adipocytes) as well as in vitro and in vivo into neural cells (glia, Schwann cells, and neurons) .

Cardiovascular System. b8 _- l- y5 ]
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Recent research has suggested that latent populations of cardiac precursors exist in the adult myocardium. More than 93% of adult cardiac SP cells are Sca-1 CD45¨CCD34¨C, exhibit levels of telomerase expression similar to neonatal myocardium, and express cardiogenic transcription factors and do not express cardiac structural genes until stimulated to differentiate in vitro . However, in all cases the selected Sca-1  populations differed in their gene expression profiles." t3 i5 ?7 N$ y- i. w9 k
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Sca-1  cells may play a regenerative role following myocardial infarction (MI). The number of endogenous Sca-1 CD31¨C cells increased significantly 7 days after MI, as did the expression of Sca-1 protein . It thus remains to be determined how or whether these populations are related, and which marker(s) will be best for isolation of therapeutically relevant cardiac progenitors.

Although the origin and function of endothelial progenitor cells remain controversial, they represent another population of cardiovascular progenitors with possible therapeutic applications. Bone marrow cells expressing Sca-1 and Flk1, for example, have demonstrated endothelial differentiation both in vitro and in vivo .

Liver8 Q* `% r9 t( M% j3 i7 @

Rather than the hepatocyte proliferation that accompanies other forms of liver damage, hepatic toxins induce regeneration by bipotent hepatic oval cells, which differentiate into hepatocytes or bile duct epithelial cells . Whether these SP cells are distinct from HSCs remains a matter of debate.

Mammary Gland( P) l/ u: G" |4 Y4 N, ]4 u8 s# m
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FACS analysis revealed that 20% of murine mammary epithelial cells express Sca-1, as do 75% of SP cells .
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Other Tissues7 t" {1 G# r. g5 X- o+ p" `9 c& Q

In many tissues where Sca-1 is expressed, it remains unclear whether Sca-1  cells include tissue resident progenitors. Sca-1 expression and the SP phenotype overlap substantially in the lung (although it is unclear whether these SP Sca-1  cells express CD45 , it is unlikely that Sca-1 is expressed on brain-derived neural progenitors./ {3 r$ e2 x# J' H6 {* e
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It is crucial to note that there are many tissues where Sca-1 expression and/or SP activity have been demonstrated not to be associated with progenitor activity. In the testis, for example, conflicting transplantation studies .! k9 S; u& @! a; c( ]

Sca-1 Expression in Cancer% z1 N- N3 z) E6 s' H& B/ D
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A variety of murine cancers including retinoblastoma .. f0 T2 u3 ~7 Z3 j0 g
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It is widely believed that receptor-ligand interactions underlie the function of many Ly6 proteins, potentially mediating cell-cell adhesion and signaling. Overexpression of Sca-1 (CD2:Ly6a.2) in mouse T cells led to self-aggregation and adherence to nontransgenic B and T cells in vitro .2 E1 N1 k8 b- ]0 O% T; u
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The generation of Sca-1 null mice by our lab  have enabled a more physiologically relevant analysis of Sca-1 function in a variety of tissues. Although both alleles of Sca-1 null mice appear phenotypically normal, careful phenotyping has demonstrated a number of defects associated with tissue-resident stem and progenitor cell populations. It is important to note that subtle differences between the two alleles of Sca-1 deficient mice may exist due to the different strategies employed in their creation, and that these dissimilarities may be magnified on various background strains.

Contrary to most expectations, based on cross-linking experiments, that Sca-1 induces lymphocyte proliferation, analysis of Sca-1 null mice demonstrated that Sca-1 functions to downregulate T-cell proliferation. Sca-1 null T cells exhibited significantly higher and more prolonged proliferation in response to T cell receptor-mediated activation, both in vitro and in vivo .' M' m% M( d7 F% v- r+ X2 {; S8 B

Hematopoiesis has been analyzed in both strains of Sca-1 null mice. Sca-1¨C/¨C mice demonstrated some minor hematopoietic lineage skewing, including reduced platelets and megakaryocytes . Although the mechanism by which Sca-1 influences cell fate determination remains unknown, we hypothesize that this occurs through altered cell signaling in lipid rafts, as discussed below in Enigmas.% P* m* [6 L% E

In vitro (CFU-granulocyte-erythroid-macrophage-megakaryocyte) and in vivo (CFU-S) clonogenic assays revealed a slight reduction in the frequency of immature Sca-1¨C/¨C hematopoietic progenitors . To evaluate HSC self-renewal in the absence of homing effects, Bradfute and colleagues challenged bone marrow chimeras to three rounds of 5-fluorouracil (FU) injections, killing cycling cells, over a 10-week period. Since the percentage of Sca-1¨C/¨C peripheral bloo
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