Dysregulation of Mitochondrial Functions and Osteogenic Differentiation in Cisd2-Deficient Murine Induced Pluripotent Stem Cells

Ping Hsing Tsai, Yueh Chien, Jen Hua Chuang, Shih Jie Chou, Chian-Shiu Chien, Ying Hsiu Lai, Hsin Yang Li, Yu Lin Ko, Yuh Lih Chang, Chen Ying Wang, Yung Yang Liu, Hsin Chen Lee, Chang Hao Yang, Ting Fen Tsai, Yi Yen Lee, Shih Hwa Chiou*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Wolfram syndrome 2 (WFS2) is a premature aging syndrome caused by an irreversible mitochondria-mediated disorder. Cisd2, which regulates mitochondrial electron transport, has been recently identified as the causative gene of WFS2. The mouse Cisd2 knockout (KO) (Cisd2-/-) recapitulates most of the clinical manifestations of WFS2, including growth retardation, osteopenia, and lordokyphosis. However, the precise mechanisms underlying osteopenia in WFS2 and Cisd2 KO mice remain unknown. In this study, we collected embryonic fibroblasts from Cisd2-deficient embryos and reprogrammed them into induced pluripotent stem cells (iPSCs) via retroviral transduction with Oct4/Sox2/Klf4/c-Myc. Cisd2-deficient mouse iPSCs (miPSCs) exhibited structural abnormalities in their mitochondria and an impaired proliferative capability. The global gene expression profiles of Cisd2+/+, Cisd2+/-, and Cisd2-/- miPSCs revealed that Cisd2 functions as a regulator of both mitochondrial electron transport and Wnt/β-catenin signaling, which is critical for cell proliferation and osteogenic differentiation. Notably, Cisd2-/- miPSCs exhibited impaired Wnt/β-catenin signaling, with the downregulation of downstream genes, such as Tcf1, Fosl1, and Jun and the osteogenic regulator Runx2. Several differentiation markers for tridermal lineages were globally impaired in Cisd2-/- miPSCs. Alizarin red S staining and flow cytometry analysis further revealed that Cisd2-/- miPSCs failed to undergo osteogenic differentiation. Taken together, our results, as determined using an miPSC-based platform, have demonstrated that Cisd2 regulates mitochondrial function, proliferation, intracellular Ca2+ homeostasis, and Wnt pathway signaling. Cisd2 deficiency impairs the activation of Wnt/β-catenin signaling and thereby contributes to the pathogeneses of osteopenia and lordokyphosis in WFS2 patients.

Original languageEnglish
Pages (from-to)2561-2576
Number of pages16
JournalStem Cells and Development
Issue number21
StatePublished - 1 Nov 2015


Dive into the research topics of 'Dysregulation of Mitochondrial Functions and Osteogenic Differentiation in Cisd2-Deficient Murine Induced Pluripotent Stem Cells'. Together they form a unique fingerprint.

Cite this