Arjun Saha
Duke University
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Featured researches published by Arjun Saha.
Cell Death and Disease | 2012
Hemangi Patil; Nomingerel Tserentsoodol; Arjun Saha; Ying Hao; Mason Webb; Paulo A. Ferreira
The retinitis pigmentosa GTPase regulator (RPGR) and nephrocystin-4 (NPHP4) comprise two key partners of the assembly complex of the RPGR-interacting protein 1 (RPGRIP1). Mutations in RPGR and NPHP4 are linked to severe multisystemic diseases with strong retinal involvement of photoreceptor neurons, whereas those in RPGRIP1 cause the fulminant photoreceptor dystrophy, Leber congenital amaurosis (LCA). Further, mutations in Rpgrip1 and Nphp4 suppress the elaboration of the outer segment compartment of photoreceptor neurons by elusive mechanisms, the understanding of which has critical implications in uncovering the pathogenesis of syndromic retinal dystrophies. Here we show RPGRIP1 localizes to the photoreceptor connecting cilium (CC) distally to the centriole/basal body marker, centrin-2 and the ciliary marker, acetylated-α-tubulin. NPHP4 abuts proximally RPGRIP1, RPGR and the serologically defined colon cancer antigen-8 (SDCCAG8), a protein thought to partake in the RPGRIP1 interactome and implicated also in retinal–renal ciliopathies. Ultrastructurally, RPGRIP1 localizes exclusively throughout the photoreceptor CC and Rpgrip1nmf247 photoreceptors present shorter cilia with a ruffled membrane. Strikingly, Rpgrip1nmf247 mice without RPGRIP1 expression lack NPHP4 and RPGR in photoreceptor cilia, whereas the SDCCAG8 and acetylated-α-tubulin ciliary localizations are strongly decreased, even though the NPHP4 and SDCCAG8 expression levels are unaffected and those of acetylated-α-tubulin and γ-tubulin are upregulated. Further, RPGRIP1 loss in photoreceptors shifts the subcellular partitioning of SDCCAG8 and NPHP4 to the membrane fraction associated to the endoplasmic reticulum. Conversely, the ciliary localization of these proteins is unaffected in glomeruli or tubular kidney cells of Rpgrip1nmf247, but NPHP4 is downregulated developmentally and selectively in kidney cortex. Hence, RPGRIP1 presents cell type-dependent pathological effects crucial to the ciliary targeting and subcellular partitioning of NPHP4, RPGR and SDCCAG8, and acetylation of ciliary α-tubulin or its ciliary targeting, selectively in photoreceptors, but not kidney cells, and these pathological effects underlie photoreceptor degeneration and LCA.
JCI insight | 2016
Arjun Saha; Susan Buntz; Paula Scotland; Li Xu; Pamela K. Noeldner; Sachit Patel; Amy Wollish; Aruni Gunaratne; Tracy Gentry; Jesse D. Troy; Glenn K. Matsushima; Joanne Kurtzberg; Andrew E. Balber
Microglia and monocytes play important roles in regulating brain remyelination. We developed DUOC-01, a cell therapy product intended for treatment of demyelinating diseases, from banked human umbilical cord blood (CB) mononuclear cells. Immunodepletion and selection studies demonstrated that DUOC-01 cells are derived from CB CD14+ monocytes. We compared the ability of freshly isolated CB CD14+ monocytes and DUOC-01 cells to accelerate remyelination of the brains of NOD/SCID/IL2Rγnull mice following cuprizone feeding-mediated demyelination. The corpus callosum of mice intracranially injected with DUOC-01 showed enhanced myelination, a higher proportion of fully myelinated axons, decreased gliosis and cellular infiltration, and more proliferating oligodendrocyte lineage cells than those of mice receiving excipient. Uncultured CB CD14+ monocytes also accelerated remyelination, but to a significantly lesser extent than DUOC-01 cells. Microarray analysis, quantitative PCR studies, Western blotting, and flow cytometry demonstrated that expression of factors that promote remyelination including PDGF-AA, stem cell factor, IGF1, MMP9, MMP12, and triggering receptor expressed on myeloid cells 2 were upregulated in DUOC-01 compared to CB CD14+ monocytes. Collectively, our results show that DUOC-01 accelerates brain remyelination by multiple mechanisms and could be beneficial in treating demyelinating conditions.
Stem Cells Translational Medicine | 2018
Arjun Saha
4 We developed a cell therapy product, DUOC-01, derived from banked human umbilical cord blood, to treat demyelinating conditions in the central nervous system. Previously, we demonstrated that DUOC-01 increased myelination and decreased gliosis and cellular infiltration in the corpus callosum of immune-incompetent mice treated with cuprizone. To investigate the mechanism and test whether DUOC-01 will be efficacious in other models of demyelination, we tested DUOC-01 in lysophosphatidylcholine (LPC) demyelinated murine organotypic cerebellar brain slices and a mouse model of experimental autoimmune encephalomyelitis (EAE). In the cerebellar brain slice culture model, we found that DUOC-01 treatment enhanced remyelination of LPC-mediated demyelinated neurons compared with the untreated control samples. These data demonstrate that DUOC-01 is capable of accelerating the remyelination of neurons by reducing gliosis and promoting oligodendrocyte proliferation and promoting myelin debris clearance. Currently, we are testing the ability of DUOC-01 to limit inflammation in EAE. Also, we are analyzing single cell sequencing data to determine various populations present in DUOC-01 cultures and to understand the functional pathways responsible for promoting remyelination. Overall, our data suggest that DUOC-01 could be beneficial in treating demyelinating conditions. STEM CELLS TRANSLATIONAL MEDICINE | StemCellsTM.com
Cytotherapy | 2017
Paula Scotland; Susan Buntz; Pamela K. Noeldner; Arjun Saha; Tracy Gentry; Joanne Kurtzberg; Andrew E. Balber
BACKGROUND AIMS DUOC-01, a cell product being developed to treat demyelinating conditions, is composed of macrophages that arise from CD14+ monocytes in the mononuclear cell (MNC) population of banked cord blood (CB). This article demonstrates that expression of multiple gene products that promote remyelination is rapidly up-regulated during manufacturing of DUOC-01 from either MNC or purified CB CD14+ monocytes. METHODS Cell cultures were initiated with MNC or with immunoselected CD14+ monocytes isolated from the same CB unit. Cell products present in these cultures after 2 and 3 weeks were compared by three methods. First, quantitative polymerase chain reaction was used to compare expression of 77 transcripts previously shown to be differentially expressed by freshly isolated, uncultured CB CD14+ monocytes and DUOC-01. Second, accumulation of 16 soluble proteins in the culture medium was measured by Bioplex methods. Third, whole transcriptomes of the cell products were compared by microarray analysis. RESULTS Key transcripts in multiple pathways that promote remyelination were up-regulated in DUOC-01, and substantial secretion of proteins corresponding to many of these transcripts was detected. Cell products manufactured from MNC or from CD14+ monocytes were similar with regard to all metrics. Upregulation of gene products characteristic of DUOC-01 was largely completed within 14 days of culture. CONCLUSION We demonstrate that expression of multiple gene products that promote remyelination is up-regulated during the first 2 weeks of manufacturing of DUOC-01. Measuring these mechanistically important transcripts and proteins will be useful in monitoring manufacturing, evaluating manufacturing changes, and developing mechanism-based product potency assays.
Journal of Biological Chemistry | 2014
Hemangi Patil; Arjun Saha; Eugene Senda; Kyoung In Cho; MdEmdadul Haque; Minzhong Yu; Sunny Qiu; Dosuk Yoon; Ying Hao; Neal S. Peachey; Paulo A. Ferreira
Cytotherapy | 2018
Arjun Saha; L. Xu; Paula Scotland; Susan Buntz; R. Franczak; Joanne Kurtzberg; Andrew E. Balber
Cytotherapy | 2018
Anthony J. Filiano; Arjun Saha; H. Min; L. Xu; M. Lillich; R. Parrott; A. Gunaratne; Pamela Noldner; N. Meadows; A. Rudisill; Joanne Kurtzberg
Biology of Blood and Marrow Transplantation | 2017
Jessica Sun; Joanne Kurtzberg; Vinod K. Prasad; Suhag Parikh; Kristin Page; Arjun Saha
Archive | 2015
Neal S. Peachey; Alan D. Marmorstein; Minzhong Yu; Weilin Zou; Thomas M. McIntyre; Jinbo Liu; Sunny Qiu; Paulo A. Ferreira; Hemangi Patil; Arjun Saha; Eugene Senda; Kyoung-in Cho; Ivy S. Samuels; Brent A. Bell; Ariane Pereira; Joseph Saxon
Cytotherapy | 2015
Arjun Saha; Susan Buntz; Sachit Patel; Marcia Bentz; David Snyder; April Ozamiz; Benjamin Rusche; Tracy Gentry; Matsushima Glenn; Joanne Kurtzberg; Andrew E. Balber