From left to right: Thulaj Meharwade, Loick Joumier and Mohan Malleshaiah.
A new Montreal Clinical Research Institute (IRCM) study discovers a promising way to enhance the potentials of Pluripotent Stem Cells such as Embryonic Stem Cells, commonly used for regenerative medicine applications. The research team has discovered that such stem cells can be chemically reprogrammed (or rolled back in time) to the very beginning or 1st stage of embryo development, enhancing their developmental or differentiation potential.
This promising work has been published in the Journal Cell Reports, and was led by Dr. Mohan Malleshaiah, Director of Stem Cells and Cell Reprogramming Research Unit at the IRCM and Assistant Professor at the Department of Biochemistry and Molecular Medicine, University of Montreal.
Study details
Pluripotent Stem Cells such as Embryonic Stem Cells and induced Pluripotent Stem Cells (iPSC) can be cultured in a dish and have the potential to differentiate into multiple embryonic cell types of an organism (cardiac cells, muscle cells, neurons, etc.) under the right circumstances. As a result, they are increasingly used for regenerative medicine, and personalized disease modelling and drug discovery applications.
Although Pluripotent Stem Cells hold great promise, they have two major limitations.
1) They lack the ability to generate extra-embryonic cell types (placenta, yolk sac, etc.). As opposed to the “pluri” potential of these cells, the “total” potential (ability to generate both embryonic and extra-embryonic cell types) is harbored by the cells at the very beginning of embryo development. However, these “Totipotent Stem Cells” are very difficult to culture in a dish, hampering their use. Thus, development of new methods is required to take advantage of the high differentiation potential of Totipotent Stem Cells.
2) Pluripotent Stem Cells are highly heterogeneous in culture; in the sense they continuously fluctuate between more and less differentiated states. This nature can compromise the efficiency of their differentiation as well as the quality of cell types generated. Thus, it is critical to control their heterogeneity to boost their applications.
In their efforts to address both issues, Dr. Malleshaiah’s team has found a unique way to generate Totipotent Stem Cells from Pluripotent Stem Cells and at the same time reduce stem cell heterogeneity, by using mouse Embryonic Stem Cells as a model system.
“We first identified that BMP signalling pathway induces the Totipotent state of stem cells. Interestingly, we also found that the function of BMP signalling for totipotency was hidden as it also activated other signalling pathways such as FGF, NODAL and WNT. Then we designed a chemical approach to activate BMP pathway but prevent activation of other pathways. This led us to successfully reprogram Pluripotent Stem Cells to functional Totipotent Stem Cells,” explains Thulaj Meharwade, a first author of the study and a doctoral student in Dr. Malleshaiah lab.
“The chemical reprogramming approach we designed in this study is also exciting since it prevented differentiated states of stem cells at the single-cell level. It reduced the overall cellular heterogeneity by about half. Also, the chemical approach to cellular reprogramming is promising over genetic approaches as it is more feasible and reversible,” explains Loick Joumier who is also a doctoral student in Dr. Malleshaiah lab and a co-first author of the study.
As next steps, the researchers are further optimizing the efficiency of the reprogramming approach and performing in-depth characterization of the reprogrammed Totipotent Stem Cells.
Funding
This work was supported through the funding from Canadian Institutes of Health Research (CIHR), Fonds de recherche du Québec – Sante (FRQS), Canada Foundation for Innovation (CFI) and IRCM Foundation.
