A Glycovariant of Human CD44 is Characteristically Expressed on Human Mesenchymal Stem Cells.
A Glycovariant of Human CD44 is Characteristically Expressed on Human Mesenchymal Stem Cells.
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DOI：
10.1002/stem.2549
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发表时间：
2017-04
期刊：
影响因子：
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通讯作者：
Sackstein R
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文献类型：
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作者：
Pachón-Peña G;Donnelly C;Ruiz-Cañada C;Katz A;Fernández-Veledo S;Vendrell J;Sackstein R
系统给药的人间充质干细胞（hMSCs）的临床效果取决于其参与血管内皮的能力。来源于骨髓的hMSCs （BM-hMSCs）天生缺乏内皮结合能力，但表达含有n -连接唾液基乳胺的CD44糖变异体，该糖变异体可以通过focusyltransferase-VI （FTVI）进行α(1,3)-聚焦，以加强sLeX修饰，从而产生造血细胞E-/ l -选择素配体（HCELL）。HCELL表达计划了表达e -选择素的循环细胞对内皮床的强力抗剪切粘附。脂质干细胞的另一种来源是脂肪组织（A-hMSCs），我们评估了A-hMSCs是否结合e-选择素和/或具有可被α(1,3)-聚焦化的唾液酰基乳胺修饰的CD44。与BM-hMSCs类似，我们发现A-hMSCs天生缺乏e -选择素配体，但ftvi介导的细胞表面α(1,3)-聚焦诱导sLeX表达和e -选择素结合，继发于CD44转化为HCELL。此外，α(1,3)-聚焦转移酶FTVII也在BM-hMSCs和A-hMSCs上产生了HCELL的表达，并在“标准”CD44 （CD44s）亚型的n -链聚糖上产生了sLeX修饰。来自两种来源组织的hMSCs均缺乏天然e -选择素配体的表达，这一发现促使人们检查指导乳胺基聚糖合成的糖基转移酶的表达。这些研究表明，两种类型的hMSCs都明显缺乏编码α(1,3)-聚焦转移酶的转录本，但同样表达对唾液基乳胺的产生至关重要的糖基转移酶。总的来说，这些数据表明，唾液酰乳胺基修饰的CD44s糖变异体的组装是来自脂肪组织和骨髓的hMSCs的保守特征，从而鉴定了这些细胞的CD44糖标记，并支持细胞表面α(1,3)-聚焦化在系统给予的a -hMSCs迁移到组织损伤/炎症部位的适应性。应用糖基转移酶程序性立体取代（GPS）增强HCELL表达。细胞表面的CD44可以通过GPS的聚糖工程转化为HCELL糖型。注意聚糖结构（包括sLeX）和通过α(1,3)-“受体”唾液化CD44在hMSC膜上的聚焦产生HCELL的策略中的组成步骤。如图所示，Gal和GlcNAc之间的“β1-4”键定义了“2型”乳胺单元。当这种结构在与n -乙酰氨基葡萄糖的1,3连锁中包含一个焦点取代时，它被称为“唾液化Lewis x”（sLeX）：用focusyltransferase VI （FTVI）或focusyltransferase VII （FTVII）处理hMSCs，可以驱动CD44聚糖的α(1,3)-聚焦化，从而产生sLeX，从而产生HCELL。数据表明，唾液基乳胺基修饰的CD44s糖变异体的组装是来自脂肪组织和骨髓的hMSCs的保守特征，从而鉴定了这些细胞的CD44糖标记，并支持细胞表面α(1,3)-聚焦化在系统给予的a -hMSCs迁移到组织损伤/炎症部位的适应性。颜色键值对应各自的单糖。
The clinical effectiveness of systemically-administered human mesenchymal stem cells (hMSCs) depends on their capacity to engage vascular endothelium. hMSCs derived from bone marrow (BM-hMSCs) natively lack endothelial binding capacity but express a CD44 glycovariant containing N-linked sialyllactosamines that can be α(1,3)-fucosylated using fucosyltransferase-VI (FTVI) to enforce sLeX decorations, thereby creating hematopoietic cell E-/L-selectin ligand (HCELL). HCELL expression programs potent shear-resistant adhesion of circulating cells to endothelial beds expressing E-selectin. An alternative source of hMSCs is adipose tissue (A-hMSCs), and we assessed whether A-hMSCs bind E-selectin and/or possess sialyllactosamine-decorated CD44 accessible to α(1,3)-fucosylation. Similar to BM-hMSCs, we found that A-hMSCs natively lack E-selectin ligands, but FTVI-mediated cell surface α(1,3)-fucosylation induces sLeX expression and robust E-selectin binding secondary to conversion of CD44 into HCELL. Moreover, treatment with the α(1,3)-fucosyltransferase FTVII also generated expression of HCELL on both BM-hMSCs and A-hMSCs, with sLeX decorations created on N-linked glycans of the "standard" CD44 (CD44s) isoform. The finding that hMSCs from both source tissues each lack native E-selectin ligand expression prompted examination of the expression of glycosyltransferases that direct lactosaminyl glycan synthesis. These studies reveal that both types of hMSCs conspicuously lack transcripts encoding α(1,3)-fucosyltransferases but equally express glycosyltransferases critical to creation of sialyllactosamines. Collectively, these data indicate that assembly of a sialyllactosaminyl-decorated CD44s glycovariant is a conserved feature of hMSCs derived from adipose tissue and marrow, thus identifying a CD44 glycosignature of these cells and supporting the applicability of cell surface α(1,3)-fucosylation in programming migration of systemically-administered A-hMSCs to sites of tissue injury/inflammation. Application of Glycosyltransferase-Programmed Stereosubstitution (GPS) to enforce HCELL expression. Cell surface CD44 can be converted to the HCELL glycoform by glycan engineering via GPS. Note glycan structures (including sLeX) and component steps in the strategy to create HCELL by α(1,3)-fucosylation of “acceptor” sialylated CD44 on the hMSC membrane. The “β1-4” linkage as shown between Gal and GlcNAc defines a “Type 2” lactosamine unit. When this structure contains a fucose substitution in a 1,3-linkage to N-acetylglucosamine it is known as ‘sialylated Lewis x’ (sLeX): Treatment of hMSCs with either fucosyltransferase VI (FTVI) or fucosyltransferase VII (FTVII) drives α(1,3)-fucosylation of CD44 glycans, thereby generating sLeX and, accordingly, engendering HCELL. Data indicate that assembly of a sialyllactosaminyl-decorated CD44s glycovariant is a conserved feature of hMSCs derived from adipose tissue and marrow, thus identifying a CD44 glycosignature of these cells and supporting the applicability of cell surface α(1,3)-fucosylation in programming migration of systemically-administered A-hMSCs to sites of tissue injury/inflammation. Color key figures correspond to respective monosaccharides.