Restoration of Physiologically Responsive Low-Density Lipoprotein Receptor-Mediated Endocytosis in Genetically Deficient Induced Pluripotent Stem Cells View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-08-26

AUTHORS

Venkat M. Ramakrishnan, Jeong-Yeh Yang, Kevin T. Tien, Thomas R. McKinley, Braden R. Bocard, John G. Maijub, Patrick O. Burchell, Stuart K. Williams, Marvin E. Morris, James B. Hoying, Richard Wade-Martins, Franklin D. West, Nolan L. Boyd

ABSTRACT

Acquiring sufficient amounts of high-quality cells remains an impediment to cell-based therapies. Induced pluripotent stem cells (iPSC) may be an unparalleled source, but autologous iPSC likely retain deficiencies requiring correction. We present a strategy for restoring physiological function in genetically deficient iPSC utilizing the low-density lipoprotein receptor (LDLR) deficiency Familial Hypercholesterolemia (FH) as our model. FH fibroblasts were reprogrammed into iPSC using synthetic modified mRNA. FH-iPSC exhibited pluripotency and differentiated toward a hepatic lineage. To restore LDLR endocytosis, FH-iPSC were transfected with a 31 kb plasmid (pEHZ-LDLR-LDLR) containing a wild-type LDLR (FH-iPSC-LDLR) controlled by 10 kb of upstream genomic DNA as well as Epstein-Barr sequences (EBNA1 and oriP) for episomal retention and replication. After six months of selective culture, pEHZ-LDLR-LDLR was recovered from FH-iPSC-LDLR and transfected into Ldlr-deficient CHO-a7 cells, which then exhibited feedback-controlled LDLR-mediated endocytosis. To quantify endocytosis, FH-iPSC ± LDLR were differentiated into mesenchymal cells (MC), pretreated with excess free sterols, Lovastatin, or ethanol (control), and exposed to DiI-LDL. FH-MC-LDLR demonstrated a physiological response, with virtually no DiI-LDL internalization with excess sterols and an ~2-fold increase in DiI-LDL internalization by Lovastatin compared to FH-MC. These findings demonstrate the feasibility of functionalizing genetically deficient iPSC using episomal plasmids to deliver physiologically responsive transgenes. More... »

PAGES

13231

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/srep13231

DOI

http://dx.doi.org/10.1038/srep13231

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1023370425

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/26307169


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25 schema:description Acquiring sufficient amounts of high-quality cells remains an impediment to cell-based therapies. Induced pluripotent stem cells (iPSC) may be an unparalleled source, but autologous iPSC likely retain deficiencies requiring correction. We present a strategy for restoring physiological function in genetically deficient iPSC utilizing the low-density lipoprotein receptor (LDLR) deficiency Familial Hypercholesterolemia (FH) as our model. FH fibroblasts were reprogrammed into iPSC using synthetic modified mRNA. FH-iPSC exhibited pluripotency and differentiated toward a hepatic lineage. To restore LDLR endocytosis, FH-iPSC were transfected with a 31 kb plasmid (pEHZ-LDLR-LDLR) containing a wild-type LDLR (FH-iPSC-LDLR) controlled by 10 kb of upstream genomic DNA as well as Epstein-Barr sequences (EBNA1 and oriP) for episomal retention and replication. After six months of selective culture, pEHZ-LDLR-LDLR was recovered from FH-iPSC-LDLR and transfected into Ldlr-deficient CHO-a7 cells, which then exhibited feedback-controlled LDLR-mediated endocytosis. To quantify endocytosis, FH-iPSC ± LDLR were differentiated into mesenchymal cells (MC), pretreated with excess free sterols, Lovastatin, or ethanol (control), and exposed to DiI-LDL. FH-MC-LDLR demonstrated a physiological response, with virtually no DiI-LDL internalization with excess sterols and an ~2-fold increase in DiI-LDL internalization by Lovastatin compared to FH-MC. These findings demonstrate the feasibility of functionalizing genetically deficient iPSC using episomal plasmids to deliver physiologically responsive transgenes.
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33 CHO
34 DNA
35 Deficient Induced Pluripotent Stem Cells
36 DiI-LDL
37 DiI-LDL internalization
38 Epstein-Barr sequences
39 FH fibroblasts
40 FH-MC
41 FH-iPSC
42 Genetically Deficient Induced Pluripotent Stem Cells
43 LDLR
44 LDLR endocytosis
45 Ldlr-deficient CHO
46 Responsive Low-Density Lipoprotein Receptor
47 amount
48 autologous iPSC
49 cell-based therapies
50 cells
51 correction
52 culture
53 deficiency
54 deficiency Familial Hypercholesterolemia
55 deficient iPSC
56 endocytosis
57 episomal plasmids
58 episomal retention
59 ethanol
60 excess free sterols
61 excess sterols
62 familial hypercholesterolemia
63 feasibility
64 feedback-controlled LDLR
65 fibroblasts
66 findings
67 fold increase
68 free sterols
69 function
70 genomic DNA
71 hepatic lineage
72 high-quality cells
73 hypercholesterolemia
74 iPSCs
75 impediments
76 increase
77 induced pluripotent stem cells
78 internalization
79 kb
80 kb plasmid
81 lineages
82 lipoprotein receptor
83 lipoprotein receptor (LDLR) deficiency Familial Hypercholesterolemia
84 lovastatin
85 low-density lipoprotein receptor
86 low-density lipoprotein receptor (LDLR) deficiency Familial Hypercholesterolemia
87 mRNA
88 mediated endocytosis
89 mesenchymal cells
90 model
91 months
92 pEHZ-LDLR
93 physiological functions
94 physiological responses
95 plasmid
96 pluripotency
97 pluripotent stem cells
98 receptor (LDLR) deficiency Familial Hypercholesterolemia
99 receptors
100 replication
101 response
102 responsive transgenes
103 restoration
104 retention
105 selective culture
106 sequence
107 source
108 stem cells
109 sterols
110 strategies
111 sufficient amount
112 synthetic
113 therapy
114 transgene
115 unparalleled source
116 upstream genomic DNA
117 wild-type LDLR
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