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• W2009791343 abstract "Stem cell-based regeneration depends partly on the delivery of stem cells to the damaged area. Recently in Nature Medicine, Sackstein et al., 2008Sackstein R. Merzaban J.S. Cain D.W. Dagia N.M. Spencer J.A. Lin C.P. Wohlgemuth R. Nat. Med. 2008; 14: 181-187Crossref PubMed Scopus (432) Google Scholar report that ex vivo fucosylation of surface CD44 promoted efficient adhesive interactions of manipulated mesenchymal stem cells with marrow vasculature and subsequent homing to endosteal surfaces. Stem cell-based regeneration depends partly on the delivery of stem cells to the damaged area. Recently in Nature Medicine, Sackstein et al., 2008Sackstein R. Merzaban J.S. Cain D.W. Dagia N.M. Spencer J.A. Lin C.P. Wohlgemuth R. Nat. Med. 2008; 14: 181-187Crossref PubMed Scopus (432) Google Scholar report that ex vivo fucosylation of surface CD44 promoted efficient adhesive interactions of manipulated mesenchymal stem cells with marrow vasculature and subsequent homing to endosteal surfaces. Multipotent stem cells, whether somatic or embryonic stem cell-derived, possess a great capacity for tissue regeneration. In clinical settings, the optimal route for administration of stem cells depends on the anatomy and the extent of damage of the involved tissue or organ, offering a choice between two approaches: direct local or intralesional implantation versus systemic intravascular administration. Although feasible for tissues with defined anatomic boundaries, local implantation is invasive, has associated procedure-related costs, and could result in significant morbidity. Moreover, this approach could disrupt a highly complex and delicate structure of the local regulatory microenvironment, i.e., the niche, causing additional traumatic injury and inflammation. Another limitation for the local administration of stem cells is the multifocality of many disorders such as generalized neurologic diseases (e.g., multiple sclerosis and amyotrophic lateral sclerosis), muscular diseases (e.g., Duchenne's muscular dystrophy), and skeletal diseases (e.g., osteoporosis and osteogenesis imperfecta). Thus, stem cell-based therapy of “systemic” disorders mandates vascular delivery. However, this approach is limited by the difficulty of ensuring that sufficient numbers of reconstituting cells reach the damaged areas in cases of ineffective stem cell homing. Fulfilling the promise of regenerative medicine, therefore, critically depends first on identifying the range of molecules that mediate organ-specific stem cell homing and second on manipulating their activity (for review, see Mooney and Vandenburgh, 2008Mooney D.J. Vandenburgh H. Cell Stem Cell. 2008; 2 (this issue): 205-213Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar, this issue of Cell Stem Cell). The recent study by Sackstein and colleagues (Sackstein et al., 2008Sackstein R. Merzaban J.S. Cain D.W. Dagia N.M. Spencer J.A. Lin C.P. Wohlgemuth R. Nat. Med. 2008; 14: 181-187Crossref PubMed Scopus (432) Google Scholar) reports new insights into the function of CD44 as a homing molecule for bone marrow-derived mesenchymal stem cells (MSC). While homing of cells involves a cascade of events, the critical initial step is a process known as “rolling,” whereby migrating cells engage in shear-resistant, low-affinity interactions with vascular endothelial cells (Butcher, 1991Butcher E.C. Cell. 1991; 67: 1033-1036Abstract Full Text PDF PubMed Scopus (2466) Google Scholar). The process of rolling is essential for cell homing since it selectively slows down subsets of circulating cells (out of the larger population of all fast-flowing cells), allowing their subsequent endothelial adhesion and transmigration under conditions of physiological shear stress. While many mechanism(s) regulating homing of nonhematopoietic stem cells remain illusive, Sackstein and colleagues addressed this key aspect of MSC biology and demonstrated that a distinct glycoform of CD44 mediates trafficking of human MSCs to bone through interactions with E-selectin, which is constitutively present on marrow vasculature. CD44 adhesion molecules represent a large family of transmembrane glycoproteins. Alternatively spliced additional exons may be inserted into the extracellular domain of CD44, determining the structure and differential function of the multiple CD44 splice variants (Khaldoyanidi et al., 2002Khaldoyanidi S. Karakhanova S. Sleeman J. Herrlich P. Ponta H. Blood. 2002; 99: 3955-3961Crossref PubMed Scopus (31) Google Scholar). Further complexity of this family of adhesion molecules is determined by the fact that the extracellular domain of CD44 also contains N- and O-linked glycosylation sites, yielding various glycoforms of CD44. Importantly, the ligand-binding affinity of CD44 depends on its glycosylation pattern (Katoh et al., 1995Katoh S. Zheng Z. Oritani K. Shimozato T. Kincade P.W. J. Exp. Med. 1995; 182: 419-429Crossref PubMed Scopus (224) Google Scholar). Previous studies performed in Sackstein's laboratory demonstrate that a sialofucosylated glycoform of CD44 expressed on human hematopoietic cells and called hematopoietic cell E-/L-selectin ligand (HCELL) was a potent E-selectin ligand (Dimitroff et al., 2000Dimitroff C.J. Lee J.Y. Rafii S. Fuhlbrigge R.C. Sackstein R. J. Cell Biol. 2001; 153: 1277-1286Crossref PubMed Scopus (227) Google Scholar). In the current study, the investigators found that human MSCs display the standard (i.e., not alternatively spliced) form of CD44, which contains α-2,3-sialylated, but not α-1,3 fucosylated, glycans. To generate HCELL, Sackstein and colleagues formulated a novel in vitro protocol containing fucosyltransferase VI (FTVI), fucose residues, and associated buffers to enforce stereospecific fucosylation of CD44 without affecting viability and stemness of MSCs. HCELL expression was induced transiently (high levels sustained for only 24 hr), conferring robust rolling of MSCs on vascular E-selectin in vitro. While CD44 has multiple ligands, this receptor/ligand specificity of CD44—engineered in vitro—may offer an opportunity to direct the migration of stem cells to one organ versus another. Given that the vascular phenotype of individual tissues and organs is highly specialized (Ruoslahti and Rajotte, 2000Ruoslahti E. Rajotte D. Annu. Rev. Immunol. 2000; 18: 813-827Crossref PubMed Scopus (194) Google Scholar), it will be important to determine which vascular adhesion molecules, expressed alone or in combination, contribute to the process of homing of hematopoietic and nonhematopoietic stem cells to a particular organ. If cell surface molecules expressed on organ-specific endothelium contribute to stem cell-endothelial cell adhesive interactions, the manipulation of these “homing signatures” may allow a more precise targeting of stem cells, directing them to the damaged areas to the exclusion of undesired organs. Importantly, the in vivo studies of Sackstein and colleagues demonstrated that transient expression of HCELL was sufficient for homing of intravenously injected human MSCs to bone in NOD/SCID mice. HCELL expression was not associated with cell “trapping” or “arrest” on the marrow sinusoids, as human MSCs transmigrated, infiltrated marrow parenchyma, and integrated into the local microenvironment. The temporary expression of HCELL represents a great advantage of this novel glycan engineering technology over other methods involving gene transfection and accompanying permanent expression of the gene product. Once beyond initial contact with the endothelium, the interactions between HCELL and E-selectin are no longer required. The reversion to the native CD44 structure is advantageous, as glycosylation may negatively impact the ability of CD44 to recognize hyaluronan (HA) (Katoh et al., 1995Katoh S. Zheng Z. Oritani K. Shimozato T. Kincade P.W. J. Exp. Med. 1995; 182: 419-429Crossref PubMed Scopus (224) Google Scholar), one of the important components of the microenvironment in bone marrow (Khaldoyanidi et al., 1999Khaldoyanidi S. Moll J. Karakhanova S. Herrlich P. Ponta H. Blood. 1999; 94: 940-949Crossref PubMed Google Scholar). In addition, CD44 binds to several molecules besides HA, including osteopontin and FGF (Ponta et al., 1998Ponta H. Wainwright D. Herrlich P. Int. J. Biochem. Cell Biol. 1998; 30: 299-305Crossref PubMed Scopus (125) Google Scholar), which may be important for determining the behavior of MSCs. Thus, migrated MSCs may engage in appropriate CD44-mediated interactions within the local bone marrow microenvironment (Figure 1). The concept of the hematopoietic stem cell (HSC) niche was proposed three decades ago (Schofield, 1978Schofield R. Blood Cells. 1978; 4: 7-25PubMed Google Scholar), and distinct lines of evidence point to roles for osteoblasts, stromal fibroblast-like cells, or endothelial cells in the localization and/or regulation of HSCs. Most likely, all these and additional cell types, including bone marrow-resident macrophages, contribute to the delicate and well-tuned structure and function of the HSC niche. However, whether there are distinct or overlapping niches for HSC and MSC populations remains open to question. Regardless, there are no doubts that the local milieu—normal or diseased—directly influences the homing-supportive function of the local endothelium. This is well illustrated by one of the most-studied examples—inflammation. However, it remains to be defined how a variety of other pathological conditions affect the microenvironment in the involved organs and how these disease-induced changes influence the ability of both local and distant endothelial cells to support homing of transplanted stem cells. Knowledge of the disease-specific differences in mechanisms mediating stem cell-endothelial cell interactions will provide a basis for future patient-specific therapeutic approaches in regenerative medicine. Taken together, the elegant work published by Sackstein and colleagues (Sackstein et al., 2008Sackstein R. Merzaban J.S. Cain D.W. Dagia N.M. Spencer J.A. Lin C.P. Wohlgemuth R. Nat. Med. 2008; 14: 181-187Crossref PubMed Scopus (432) Google Scholar) provides compelling evidence that ex vivo chemical engineering of the glycosylation to create a distinct homing molecule can reprogram the migratory behavior of infused stem cells in vivo. Since E-selectin expression is induced within endothelial beds at all sites of tissue injury and because CD44 is expressed at high levels on most stem cells, strategies to “custom modify” CD44 glycans to create HCELL could be exploited to control stem cell tissue tropism. Further development of this exciting technology and other methodologies that allow manipulation of particular subsets of homing molecules is pivotal for refining organ-specific homing and stem cell-based tissue regeneration." @default.
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• W2009791343 title "Directing Stem Cell Homing" @default.
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