Glycoscience-based research that is performed expressly to address medical necessity and
June 17, 2019
Glycoscience-based research that is performed expressly to address medical necessity and improve patient outcomes is called translational glycobiology. CD44 glycans to enforce HCELL expression on viable cell surfaces. Human mesenchymal stem cells (MSCs) are devoid of E-selectin ligands, but GPS-based glycoengineering of CD44 on MSCs licenses homing of these cells to marrow a patient could in as many as 25% of patients receiving the treatment. Thus began my interest in the molecular basis of cell migration, and, in particular, my pursuit of knowledge into how HSCs home to marrow. I wondered about the homing receptor that would guide marrow migration of HSCs: what is the structure of this molecule? How does it work? Also, most importantly, given its enormous potential to life-threatening blood diseases, I was both intellectually and emotionally drawn to HSC transplantation, and this Erastin inhibition is the area of medicine in which I have dedicated my entire clinical career. In that same period of time, in the medical school classroom, I was learning about the pathobiology of infectious diseases. One particularly inspiring lecture highlighted the sentinel contributions of Robert Heinrich Herman Koch to bacterial culture techniques and to our understanding of the tubercle bacillus as the etiologic agent in tuberculosis. That lecture Mouse monoclonal to HDAC4 also described Koch’s postulates, a revolutionary advance in medical science in the late 1880s (whose origins could be traced to Jacob Henle, a mentor to Koch (Evans 1976)), whereby Koch established a standard for evidence in determining the causal relationship between a microbe and disease (Figure?1). But, for that era, well beyond its impact in microbiology, assay created by Woodruff and Hugh B. Stamper in the mid-1970s (the StamperCWoodruff assay) (Stamper and Woodruff 1976). This assay mimics physiologic binding of lymphocytes to HEV, and consists of overlaying suspensions of viable lymphocytes onto glutaraldehyde-fixed Erastin inhibition thin (typically, 10 m thickness) cryostat sections of lymph nodes, in the cold (4C7C) under shear conditions (as originally described, fluid shear delivered by a rotatory platform). In their Erastin inhibition landmark studies, these investigators correctly deduced that because lymphocyte-HEV adherence was occurring under hemodynamic flow conditions, the binding of lymphocytes to HEV would require shear stress. The fact that the assay was performed in the cold was fortuitous, as it avoided engagement of a variety of confounding adhesion molecules, particularly integrins, whose activity are blunted under sub-physiologic temperatures (Spertini et al. 1991). The StamperCWoodruff assay allowed specific and reproducible analysis of the avid adhesion between lymphocytes and HEV, and in their initial description of assay results, the authors described the lymph node homing molecule as a lymphocyte surface receptor for HEV (Stamper and Woodruff 1976). This assay then enabled studies by Stephen D. Rosen and colleagues which revealed that the lymphocyte HEV receptor was a lectin and that sialylated glycans expressed on HEV served as the ligand for this lectin (Stoolman and Rosen 1983; Rosen et al. 1985; Rosen and Yednock 1986). The StamperCWoodruff assay also facilitated the development of monoclonal antibody reagents that could neutralize the function of the receptor, initially described in the early 1980s by two investigators working separately, Yee Hon Chin, then a post-doctoral fellow working under Woodruff (Chin et al. 1983, 1984; Rasmussen et al. 1985), and by W. Michael Gallatin (Gallatin et al. 1983). The Chin mAb (known as A.11) was directed against the rat lymph node homing Erastin inhibition receptor, and the Gallatin mAb (known as MEL-14) was directed against the mouse homologue. Moreover, the StamperCWoodruff assay also allowed for development of an mAb by Philip R. Streeter called MECA79 that blocks the ability of HEV to support lymphocyte adherence (Streeter et al. 1988). The availability of the MECA79 mAb was critical to identifying a family of sulfated, sialofucosylated glycoproteins that serve as L-selectin ligands on HEV, collectively known as peripheral lymph node addressins (for review, see Rosen 2004). Throughout most of the 1980s, the identity of the authentic lymph node homing receptor was unsettled due to various conflicting Erastin inhibition results. Some investigations suggested that a protein called the Hermes antigen served as the human lymph node homing receptor (Jalkanen, Bargatze, et al. 1986; Jalkanen, Reichert, et al. 1986; Jalkanen et al. 1987), and there were.