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Modeling human early development with stem cell-based integrated embryo-like models

Project

Project Details

Program
BioEngineering
Field of Study
stem cell, developmental biology, bioengineering
Division
Biological and Environmental Sciences and Engineering
Faculty Lab Link
https://www.kaust.edu.sa/en/study/faculty/mo-li

Project Description

A peculiarity of human reproduction is the high rate of developmental failure before and after the time of embryo implantation. Understanding why early pregnancy failures occur is a significant question in the field but remains challenging due to the technical and ethical complexities involved in studying these developmental stages. Pluripotent stem cells have recently been used to construct various early developmental models that hold great promise in unlocking the mysteries of early human development and facilitating new reproductive therapies. Human blastoids are one such valuable model for studying early human development. They can be derived from naïve pluripotent stem cells and consist of all three lineages of the preimplantation blastocyst. Current methods using static batch culture to generate human blastoids have limitations, including (i) low yield, (ii) the need for cell aggregation, which complicates genetic or drug screens, (iii) reproducibility issues due to an uncontrolled cellular environment, and (iv) the requirement for Aggrewell or similar confinements that can exert unnatural geometrical strains on blastoids. Additionally, current blastoid models exhibit instabilities in the development of post-implantation lineages. The candidates of this VSRP project are expected to work on developing methods for large-scale production of human blastoids under strict environmental control, improving post-implantation lineage differentiation of blastoids, and characterizing gene expression in a spatially resolved manner in single cells. The successful outcome of the project is expected to significantly advance the development of in vitro human embryo models that faithfully recapitulate specific intricacies of embryogenesis. These models have the potential to be translated into applications in regenerative medicine, disease modeling, and personalized therapies.

About the Researcher

Mo Li
Associate Professor, Bioscience
Biological and Environmental Science and Engineering Division

Affiliations

Education Profile

  • Postdoctoral Fellow, Salk Institute for Biological Sciences, 2009
  • Ph.D., University of Georgia, 2007
  • B.Sc., Peking (Beijing) University, 2001

Research Interests

a€‹Professor Lia€˜s research attempts to understand the molecular basis of the regenerative mechanisms that maintain the proper form and function of the human body. His research programs build on a multidisciplinary platform that integrates stem cell models with genome engineering, functional genomics, bioengineering and chemical screening to gain a holistic understanding of regeneration in its broadest sense, while keeping a commitment to fulfilling the translational promise of stem cell research.

Selected Publications

  • Bi, C.; Wang, L.; Fan, Y.; Yuan, B.; Ramos-Mandujano, G.; Zhang, Y.; Alsolami, S.; Wang, J.; Shao, Y.; Reddy, P.; Zhang, P.-Y.; Huang, Y.; Yu, Y.*; Izpisua Belmonte, J.C.*; Li, M.*, Single-cell Individual Full-length mtDNA Sequencing Uncovers Unexpected Heteroplasmy Shifts in mtDNA Editing. Nucleic Acids Research, Mar 31, 2023.
  • Bi, C.; Wang, L.; Fan, Y.; Yuan, B.; Alsolami, S.; Zhang, Y.; Zhou, X.; Zhang, P.-Y.; Huang, Y.; Yu, Y.*; Izpisua Belmonte, J.C.*; Li, M.*, Quantitative Haplotype-resolved Analysis of mtDNA Heteroplasmy in Human Single Oocytes, Blastoids, and Pluripotent Stem Cells, Nucleic Acids Research, April 4, 2023.
  • Giorgetti, A.; Gu, Y.; Suzuki K.; Li, M.*, Editorial: Developmental Models 2.0. Frontiers in Cell and Developmental Biology, Oct 12, 2022
  • Yuan, B.; Zhou, X.; Suzuki K.; Ramos-Mandujano, G.; Wang, M.; Tehseen, M.; Cortes-Medina, L.; Moresco, J. J.; Dunn, S.; Hernandez-Benitez, R.; Hishida, T.; Kim, N.Y.; Andijani, M. M.; Bi, C.; Ku, M.; Takahashi, Y.; Xu, J.; Qiu, J.; Huang, L.; Benner, C.; Aizawa, E.; Qu, J.; Liu, G.H.; Li, Z.; Yi, F.; Ghosheh, Y.; Shao, C.; Shokhirev, M.; Comoli, P.; Frassoni, F.; Yates, R. J. III; Fu, XD; RodrA­guez Esteban, C; Hamdan, S.; Izpisua Belmonte, J.C.*; Li M.*, Wiskott-Aldrich Syndrome Protein Forms Nuclear Condensates and Regulates Alternative Splicing. Nature Communications, Jun 25, 2022
  • Fan, Y.; Min, Z.; Alsolami, S. M.; Ma, Z.; Zhang, E.; Chen, W.; Zhong, K.; Pei, W.; Kang, X.; Zhang, P.; Wang, Y.; Zhang, Y.; Zhan, L.; Zhu, H.; An, C.; Li, R.; Qiao, J.; Tan, T.*;, Li, M.*; Yu, Y.*, Generation of human blastocyst-like structures from pluripotent stem cells. Cell Discovery 2021, 7:81. Co-corresponding author.
  • Klein, S. G.; Alsolami, S. M.; Steckbauer, A.; Arossa, S.; Parry, A. J.; Ramos Mandujano, G.; Alsayegh, K.; Izpisua Belmonte, J. C.*; Li, M.*; Duarte, C. M.*, A prevalent neglect of environmental control in mammalian cell culture calls for best practices. Nature Biomedical Engineering 2021, 1-6. Co-corresponding author.
  • Zhang, S. ; Yuan, B. ; Lam, J. H.; Zhou, J.; Zhou, X.; Ramos-Mandujano, G.; Tian, X.; Liu, Y.; Han, R.; Li, Y.; Gao, X.*; Li, M.*; Yang, M.*, Structure of the full-length human Pannexin1 channel and insights into its role in pyroptosis. Cell Discovery 2021, 7 (1), 1-15. Co-corresponding author.
  • C Bi, G Mandujano, Y Tian, S Hala, J Xu, S Mfarrej, Y Tian, C. Rodriguez Esteban, E Nunex Delicado, F Alofi, A Khogeer, A Hashem, N Almontashiri, A Pain, JC Izpisua Belmonte, M Li, Simultaneous Detection and Mutation Surveillance of SARS-CoV-2 and co-infections of multiple respiratory viruses by Rapid field-deployable sequencing medRxiv, June 14, 2020, Published March 31, 2021, https://doi.org/10.1016/j.medj.2021.03.015, Med
  • Bi, C., Wang, L., Yuan, B., Zhou X. Li, Y., Wang, S., Pang, Y., Gao X., Huang Y., Li, M. Long-read individual-molecule sequencing reveals CRISPR-induced genetic heterogeneity in human ESCs. Genome Biol 21, 213 (2020). https://rdcu.be/b6q2K
  • G Mandujano and M Li, MARVICS: A Robust and Safe Magnetic Nanoparticle based RNA Extraction Method Compatible with Phenol-chloroform Inactivated Infectious Samples, Protocols.io, July 15, 2020, dx.doi.org/10.17504/protocols.io.bik4kcyw
  • Li M* and Izpisua Belmonte JC*. Organoids - Preclinical Models of Human Disease. New England Journal of Medicine. Feb 7, 2019. *co-corresponding author
  • Li Y, Han R, Bi C, Li M, Wang S, Gao X, DeepSimulator: a deep simulator for Nanopore sequencing, Bioinformatics, April 2, 2018, in press.
  • Li M* and Izpisua Belmonte JC*. Deconstruct pluripotency gene regulatory network. Nature Cell Biology. VOL 20, APRIL 2018, 382a-392.http://rdcu.be/J3Kw, Co-corresponding author
  • Alsaiari SK, Patil S, Alyami M, Alamoudi KO, Aleisa FA, Merzaban JS, Li M, and Khashab NM, Endosomal Escape and Delivery of CRISPR/Cas9 Genome Editing Machinery Enabled by Nanoscale Zeolitic Imidazolate Framework. Journal of the American Chemical Society 2018 140 (1), pp 143a-146 epub December 22, 2017
  • Takahashi Y, Wu J, Suzuki K, Martinez-Redondo P, Li M, Liao HK, Wu MZ, Hernandez-Benitez R, Hishida T, Shokhirev MN, Rodriguez Esteban C, Sancho-Martinez I, and Izpisua Belmonte JC. Integration of CpG-free DNA induces de novo methylation of CpG islands in pluripotent stem cells. Science 356, 503a-508 (2017) 5 May 2017 (link: http://science.sciencemag.org/content/356/6337/503.long)
  • Li M and Izpisua Belmonte JC. Ground rules of the pluripotency gene regulatory network. Nature Reviews Genetics. Published online 03 January 2017
  • Li M and Izpisua Belmonte JC. Looking to the future following ten years of induced pluripotent stem cell (iPSC) technologies. Nature Protocols. 11, 1579-1585 (2016).
  • Ocampo A, Reddy P, Martinez-Redondo P, Platero-Luengo A, Hatanaka F, Hishida T, Li M, Lam D, Kurita M, Beyret E, Araoka T, Vazquez-Ferrer E, Donoso D, Roman JL, Xu J, Rodriguez Esteban D, Nunez G, Nunez Delicado E, Campistol JM, Guillen E, Guillen P, and Izpisua Belmonte JC. In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. Cell 2016 Dec 15, 167, 1719-1733
  • Suzuki K, Tsunekawa Y, Hernandez-Benitez R, Wu J, Zhu J, Kim E, Hatanaka F, Yamamoto M, Araoka T, Li Z, Kurita M, Hishida T, Li M, Aizawa E, Chen S, Goebl A, Soligalla RD, Qu J, Jiang T, Skowronska-Krawczyk D, RodrA­guez Esteban C, Lajara J, NuA±ez E, Guillen P, Campistol J, Matsuzaki F, Liu GH, Magistretti P, Zhang K, Callaway E, Zhang K, Izpisua Belmonte JC. In vivo genome editing via CRISPR-Cas9 mediated homology-independent targeted integration Nature 540, 144a-149 (01 December 2016)

Desired Project Deliverables

1. Developing methods for large-scale production of human blastoids under strict environmental control 2. Improving post-implantation lineage differentiation of blastoids 3. characterizing gene expression in blastoids in a spatially-resolved manner in single cells

Recommended Student Background

cell biology
stem cell
developmental biology
bioengineering
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