Expression of the insulin-like growth factor-II/mannose-6-phosphate receptor in multiple human tissues during fetal life and early infancy

Abstract

The insulin like growth factor-II/mannose-6-phosphate (IGF-II/ M6P) receptor has been detected in many cells and tissues. In the rat, there is a dramatic developmental regulation of IGF-II/MGP receptor expression, the receptor being high in fetal and neonatal tissues and declining thereafter. We have systematically studied the expression of the human IGF-II/MGP receptor protein in tissues from 10 human fetuses and infants (age 23 weeks gestation to 24 months postnatal). We have asked 1) whether there is differential expression among different organs, and 2) whether or not the human IGF-II/MGP receptor is developmentally regulated from 23 weeks gestation to 24 months postnatal. Protein was extracted from human tissues using a buffer containing 2% sodium dodecyl sulfate and 2% Triton X-100. Aliquots of the protein extracts were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting using an anti-IGF-II/MGP receptor antiserum (no. 66416) and lz51-protein A or an immunoperoxidase stain. IGF-II/MGP receptor immunoreactivity was detected in all tissues studied with the highest amount of receptor being expressed in heart, thymus, and kidney and the lowest receptor content being measured in brain and muscle. The receptor content in ovary, testis, lung, and spleen was intermediate. The apparent molecular weight of the IGF-II/MGP receptor (220,000 kilos without reduction of disulfide bonds) varied among the different tissues: in brain the receptor was of lower molecular weight than in other organs. Immunoquantitation experiments employing Y-protein A and protein extracts from human kidney at different ages revealed a small, albeit not significant, difference of the receptor content between fetal and postnatal tissues: as in other species, larger amounts of receptor seemed to be present in fetal than in postnatal organs. In addition, no significant difference of the receptor content between human fetal liver and early postnatal liver was measured employing Y-protein A-immunoquantitation in three fetal and five postnatal liver tissue samples. The distribution of IGF-binding protein (IGEBP) species, another abundant and major class of IGF binding principles, was also measured in human fetal and early postnatal lung, liver, kidney, muscle, and brain using Western ligand blotting with '251-IGF-II: as with IGF-II/MGP receptor immunoreactivity there was differential expression of the different classes of IGFBPs in the various organs. In conclusion, 1) the IGF-II/MGP receptor is present in multipie human tissues, 2) the human IGF-II/MGP recentor is variablv exnressed in different organs, 3) there is a m&h lesser degree of developmental regulation of IGF-II/ M6P receptor expression in the human than has been reported for the rat or sheep, 4) the differential pattern of distribution of IGF-II/MGP receptor and IGFBPs in the various organs throughout fetal and early postnatal human life points to an important and tissue specific role of the IGF binding principles in development and growth. (J...

Carbohydrate-remodelled acid α-glucosidase with higher affinity for the cation-independent mannose 6-phosphate receptor demonstrates improved delivery to muscles of Pompe mice

“…50-60 % in the younger cohort. The increase in resistance to treatment in the older animals may be related to the reported decline in the density of cell surface CI-MPR with age [25,26]. It has also been suggested that the structure of the stored glycogen and the intracellular trafficking and lysosomal processing of the exogenous enzyme may be altered in aged Pompe cells.…”

“…Skeletal muscles also purportedly have a lower abundance of the CI-MPR (cationindependent M6P receptor, where M6P stands for mannose 6-phosphate) that is essential for cellular uptake of the lysosomal enzyme [2,25,26]. Furthermore, CHO cell-and transgenic animalderived rhGAA appear to have less optimal affinity for the CI-MPR.…”

Comparative Efficacy and Safety of Multiple Routes of Direct CNS Administration of Adeno-Associated Virus Gene Transfer Vector Serotype rh.10 Expressing the Human Arylsulfatase A cDNA to Nonhuman Primates

“…No difference was seen between the PBS versus AAV-treated NHPs [two-way repeated-measures ANOVA, p > 0.37, F(35,35) = 1.11]. (Funk et al, 1992;Ghosh et al, 2003). Intravenous administration of recombinant ARSA in the MLD mouse model reduced sulfatide storage in the brain and peripheral nerves, but was efficacious only when injected into young mice (Matzner et al, 2005;Matthes et al, 2012).…”

“…Because the vector was administered in multiple loci in this study, it was not possible to determine whether the enzyme spread was due to retrograde axonal transport of the vector or to uptake through the M6P receptor system, or occurred by an unknown mechanism (Funk et al, 1992;Ghosh et al, 2003;Kells et al, 2012). Because this was not a formal safety and toxicology study, determination of the biodistribution of the AAVrh.10 vector in the brain and visceral organs was not performed in this study; instead we focused on the efficacy-related distribution of the transgene end-product, ARSA enzyme, to specify potential therapeutic coverage across the brain as a comparison for the various routes of administration.…”

“…Because the blood-brain barrier prevents effective therapy with systemic administration of ARSA, investigators have explored the use of gene therapy to provide the missing ARSA enzyme in MLD via direct intraparenchymal administration or by the use of genetically modified bone marrow stem cells that differentiate into microglial cells in the CNS (Matzner et al, 2000;Biffi et al, 2004Biffi et al, , 2006Biffi et al, , 2013Sevin et al, 2006Sevin et al, , 2007Colle et al, 2010;Piguet et al, 2012). The CNS manifestations of MLD are ideal for a CNS gene therapy approach because the ARSA enzyme is secreted into the extracellular matrix and incorporated into neighboring and distant cells via the ubiquitous cell surface, mannose 6-phosphate (M6P) receptor (Willingham et al, 1981;Funk et al, 1992;Ghosh et al, 2003). Normal mechanisms for secretion of ARSA enzyme, the process of retrograde transport via axonal connections, and the M6P scavenger system can be leveraged to deliver the ARSA enzyme to many more cells in the CNS than those transduced with the ARSA cDNA.…”