Single-cell transcriptomics reconstructs fate conversion from fibroblast to...

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The paper for this talk: Liu Z*, Wang L*, Welch JD*, Ma H, Zhou Y, Vaseghi HR, Yu S, Wall JB, Alimohamadi S, Zheng M, Yin CY, Shen WN, Prins JF, Liu JD, Qian L (2017). Single cell transcriptomics reconstructs lineage conversion from fibroblast to cardiomyocyte. Nature, 551, 100-104 *: co-first author.

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Direct lineage conversion offers a new strategy for tissue regeneration and disease modeling. Despite recent success in directly reprogramming fibroblasts into various cell types, the precise changes that occur as fibroblasts progressively convert to the target cell fates remain unclear. The inherent heterogeneity and asynchronous nature of the reprogramming process renders it difficult to study this process using bulk genomic techniques. Here we used single-cell RNA sequencing to overcome this limitation and analysed global transcriptome changes at early stages during the reprogramming of mouse fibroblasts into induced cardiomyocytes (iCMs)1–4. Using unsupervised dimensionality reduction and clustering algorithms, we identified molecularly distinct subpopulations of cells during reprogramming. We also constructed routes of iCM formation, and delineated the relationship between cell proliferation and iCM induction. Further analysis of global gene expression changes during reprogramming revealed unexpected downregulation of factors involved in mRNA processing and splicing. Detailed functional analysis of the top candidate splicing factor, Ptbp1, revealed that it is a critical barrier for the acquisition of cardiomyocyte-specific splicing patterns in fibroblasts. Concomitantly, Ptbp1 depletion promoted cardiac transcriptome acquisition and increased iCM reprogramming efficiency. Additional quantitative analysis of our dataset revealed a strong correlation between the expression of each reprogramming factor and the progress of individual cells through the reprogramming process, and led to the discovery of new surface markers for the enrichment of iCMs. In summary, our single-cell transcriptomics approaches enabled us to reconstruct the reprogramming trajectory and to uncover intermediate cell populations, gene pathways and regulators involved in iCM induction.

Speaker Bio:

Dr.Qian (Li Qian) received her undergraduate degree in biology from Fudan University in China and a Ph.D. in molecular and cell biology from University of Michigan, Ann Arbor. She then pursued postdoctoral training in cardiovascular and stem cell biology at Gladstone Institute, UCSF. Currently as an Assistant Professor at UNC-Chapel Hill, Dr. Qian and her lab ( are exploring the reprogramming approaches to investigate the fundamental events underlying the progression of various cardiovascular diseases as well as to discover the basic mechanisms of cell reprogramming. Although still at early stage of her career, Dr. Qian has published 54 manuscripts in various peer-reviewed journals, including the ones in Nature, Cell Stem Cell, Development Cell, Cell Reports, Circulation Research, P.N.A.S. and others. As further evidence of the importance of her work, Dr. Qian has received numerous honors and awards, including the American Heart Association Katz Prize for Basic Research, and the recent Boyalife Prize in Stem Cell and Regenerative Medicine from Science/AAAS that awards globally to the most promising young stem cell biologist. Aside from research in the lab, Dr.Qian also actively participate in various educational activities for students, postdocs and the general public. The news stories highlighting her perseverance in pursuing dream in science as a female immigrant, and her balance in academic career and personal life as a mother of two have been inspiring and encouraging to many young scientists. This year, Dr.Qian has become the youngest ever faculty in UNC history to receive the Outstanding Mentor Award, to recognize her endless dedication and exceptional effort in training our next generation of scientists.

Dr. Liu (Ziqing Liu) received her undergraduate degree in Life Science from University of Science and Technology ofChina (USTC) and a Ph.D. in Microbiology and Immunology from Indiana University. She then pursued postdoctoral training in cardiovascular biology and regenerative medicine at University of North Carolina at Chapel Hill (UNC), under the mentorship of Dr. Li Qian. Her main focus in the Qian lab was to understand the cellular and molecular mechanisms of cell fate conversion from fibroblasts into induced cardiomyocytes (iCM), which is also termed as “direct cardiac reprogramming”. In the three and a halfyear postdoc training, she took the leading role in multiple interdisciplinary projects and published seven manuscripts in various peer-reviewed journals, including the ones in Nature, Cell Stem Cell, CellReports, Circulation Research, and others. Dr. Liu recently took a non-tenure track faculty position in Dr.Victoria Bautch’s lab also at UNC, where she will apply her knowledge and experience in single cellOMICs towards unraveling mechanisms of blood vessel formation and function. In the future, Dr. Liuexpect to combine her expertise in both experimental biology and computational analysis, as well as her interests in both cardiac and vascular biology, and to establish her own research program for the understanding of cell fate decisions in the cardiovascular system and their implications in cardiovascular diseases.

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