Podocytes derived from human induced pluripotent stem cells: characterization, comparison, and modeling of diabetic kidney disease View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2022-07-26

AUTHORS

Julie Bejoy, Justin M. Farry, Jennifer L. Peek, Mariana C. Cabatu, Felisha M. Williams, Richard C. Welch, Eddie S. Qian, Lauren E. Woodard

ABSTRACT

BackgroundIn diabetic kidney disease, high glucose damages specialized cells called podocytes that filter blood in the glomerulus. In vitro culture of podocytes is crucial for modeling of diabetic nephropathy and genetic podocytopathies and to complement animal studies. Recently, several methods have been published to derive podocytes from human-induced pluripotent stem cells (iPSCs) by directed differentiation. However, these methods have major variations in media composition and have not been compared.MethodsWe characterized our accelerated protocol by guiding the cells through differentiation with four different medias into MIXL1+ primitive streak cells with Activin A and CHIR for Wnt activation, intermediate mesoderm PAX8+ cells via increasing the CHIR concentration, nephron progenitors with FGF9 and Heparin for stabilization, and finally into differentiated podocytes with Activin A, BMP-7, VEGF, reduced CHIR, and retinoic acid. The podocyte morphology was characterized by scanning and transmission electron microscopy and by flow cytometry analysis for podocyte markers. To confirm cellular identity and niche localization, we performed cell recombination assays combining iPSC-podocytes with dissociated mouse embryonic kidney cells. Finally, to test iPSC-derived podocytes for the modeling of diabetic kidney disease, human podocytes were exposed to high glucose.ResultsPodocyte markers were expressed at similar or higher levels for our accelerated protocol as compared to previously published protocols that require longer periods of tissue culture. We confirmed that the human podocytes derived from induced pluripotent stem cells in twelve days integrated into murine glomerular structures formed following seven days of culture of cellular recombinations. We found that the high glucose-treated human podocytes displayed actin rearrangement, increased cytotoxicity, and decreased viability.ConclusionsWe found that our accelerated 12-day method for the differentiation of podocytes from human-induced pluripotent stem cells yields podocytes with comparable marker expression to longer podocytes. We also demonstrated that podocytes created with this protocol have typical morphology by electron microscopy. The podocytes have utility for diabetes modeling as evidenced by lower viability and increased cytotoxicity when treated with high glucose. We found that multiple, diverse methods may be utilized to create iPSC-podocytes, but closely mimicking developmental cues shortened the time frame required for differentiation. More... »

PAGES

355

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http://scigraph.springernature.com/pub.10.1186/s13287-022-03040-6

DOI

http://dx.doi.org/10.1186/s13287-022-03040-6

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https://app.dimensions.ai/details/publication/pub.1149784415

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/35883199


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49 cellular identity
50 cellular recombination
51 characterization
52 comparison
53 composition
54 concentration
55 cues
56 culture
57 cytometry analysis
58 cytotoxicity
59 damage
60 days
61 days of culture
62 developmental cues
63 diabetes modeling
64 diabetic kidney disease
65 diabetic nephropathy
66 different medias
67 differentiation
68 differentiation of podocytes
69 disease
70 diverse methods
71 electron microscopy
72 embryonic kidney cells
73 expression
74 filter blood
75 flow cytometry analysis
76 frame
77 glomerular structure
78 glomeruli
79 glucose
80 glucose damage
81 heparin
82 high glucose
83 high glucose damage
84 high levels
85 human podocytes
86 human-induced pluripotent stem cells
87 iPSCs
88 identity
89 induced pluripotent stem cells
90 kidney cells
91 kidney disease
92 levels
93 localization
94 long period
95 low viability
96 major variations
97 marker expression
98 markers
99 medias
100 medium composition
101 method
102 microscopy
103 modeling
104 morphology
105 mouse embryonic kidney cells
106 nephron progenitors
107 nephropathy
108 niche localization
109 period
110 pluripotent stem cells
111 podocyte markers
112 podocyte morphology
113 podocytes
114 podocytopathies
115 primitive streak cells
116 progenitors
117 protocol
118 rearrangement
119 recombination
120 retinoic acid
121 scanning
122 stabilization
123 stem cells
124 structure
125 study
126 time frame
127 tissue culture
128 transmission electron microscopy
129 typical morphology
130 utility
131 variation
132 viability
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