Single cell transcriptomic analysis of human pluripotent stem cell chondrogenesis

Chia-Lung Wu, Amanda Dicks, Nancy Steward, Ruhang Tang, Dakota B. Katz, Yun-Rak Choi and Farshid Guilak ()
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Chia-Lung Wu: Washington University in Saint Louis
Amanda Dicks: Washington University in Saint Louis
Nancy Steward: Washington University in Saint Louis
Ruhang Tang: Washington University in Saint Louis
Dakota B. Katz: Washington University in Saint Louis
Yun-Rak Choi: Washington University in Saint Louis
Farshid Guilak: Washington University in Saint Louis

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract The therapeutic application of human induced pluripotent stem cells (hiPSCs) for cartilage regeneration is largely hindered by the low yield of chondrocytes accompanied by unpredictable and heterogeneous off-target differentiation of cells during chondrogenesis. Here, we combine bulk RNA sequencing, single cell RNA sequencing, and bioinformatic analyses, including weighted gene co-expression analysis (WGCNA), to investigate the gene regulatory networks regulating hiPSC differentiation under chondrogenic conditions. We identify specific WNTs and MITF as hub genes governing the generation of off-target differentiation into neural cells and melanocytes during hiPSC chondrogenesis. With heterocellular signaling models, we further show that WNT signaling produced by off-target cells is responsible for inducing chondrocyte hypertrophy. By targeting WNTs and MITF, we eliminate these cell lineages, significantly enhancing the yield and homogeneity of hiPSC-derived chondrocytes. Collectively, our findings identify the trajectories and molecular mechanisms governing cell fate decision in hiPSC chondrogenesis, as well as dynamic transcriptome profiles orchestrating chondrocyte proliferation and differentiation.

Date: 2021
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DOI: 10.1038/s41467-020-20598-y

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