iPSC-derived Organoids: Tracing its Potential in Disease Modeling

Stem cell biology has always been an area of research with tremendous potential to reshape the way scientists comprehend human pathophysiology. Over the years, the scope of stem cell technologies and its applications has enthralled the biomedical research community. Current stem cell technologies provide exciting avenues to explore disease modeling, regeneration, personalized precision medicine and drug development.

One of the most fascinating, current stem cell technologies includes induced-pluripotent stem cells or iPSCs. iPSCs were first created by Japanese scientists Yamanaka and Takahashi in the early 2000s (2006-2007) in both murine and human models [1]. The creation of iPSCs entails 'reprogramming' fully differentiated somatic cells back into an 'embryonic' state where they can differentiate into other cell types [1]. The process of 'reprogramming' involves exposure to a set of transcription (Yamanaka) factors (TFs)- Sox2, Oct4, Klf4 and c-Myc through viral vectors [2]. For this remarkable contribution towards stem cell research, Yamanaka was eventually awarded the Nobel Prize in Physiology or Medicine in 2012 [1].

Once iPSCs are created, scientists can then induce the formation of a cell of interest by exposing them to a set of cell-specific markers and growth factors. There are several cellular models of iPSCs that allow for a deeper dive into the mechanisms of bodily pathologies. iPSC monocultures are the 'least complex', which contain only one cell type [1]. However, different cell types can be pooled together to create a more complex iPSC co-culture [1]. These co-cultures are particularly useful in understanding cell signaling and communication across cell types [1]. Astoundingly, in particular conditions, iPSCs can also orient themselves into 3D structures called organoids [1]. Organoids, suggestive from the name, can resemble the cellular and tissue features of human organs in vitro, to an extent [1]. As a result, iPSC-derived organoids are increasingly becoming used to further investigate disease and effects of potential drugs.

iPSCs sourced from healthy and diseased individuals can be used to create individual-specific and disease-specific organoids. A wide range of diseases have been/are being studied using organoids as models. Neurodegenerative diseases like Alzheimer's and Parkinson's can be modeled by iPSC-derived brain organoids [3]. Similarly, various genetic and non-genetic cardiovascular diseases (CVD) can be studied via iPSC-derived organoids and cardiomyocytes [4]. iPSC-derived lung organoids have been used to understand the molecular mechanisms of COVID-19 [3]. Cancer disease modeling has also been done previously using iPSCs to elucidate mechanisms of cancer progression [3].

Before we continue to talk further about iPSCs, a quick segue into the nitty-gritty aspects of stem cell biology. The (initial) intellectual buzz surrounding stem cells concerned their ability of self renewal and their potency to differentiate into other cells within the human body. Earlier, pluripotency (the capability of differentiating into most cells in the body) seemed limited to human embryonic stem cells (hESCs). The use of hESCs in biomedical research and the development of hESC-based stem cell therapies has been perpetually contested citing ethical dilemmas around embryo destruction and certain shortcomings of in vitro fertilization [3]. As a result, iPSC technologies can be perceived as a more acceptable alternative to hESC based therapies. Similarly, iPSC technologies like organoids, with time and further standardization of protocols, can also pave way for a lower reliance on animal models within biomedical research in the future [5]. While there are several advantageous aspects to the use of iPSC derived organoids in biomedical research, there are certainly limitations that cannot be overlooked. Some of the main concerns include reproducibility issues, cell specification and maturation delays, and vascularization (particularly in the case of cardiac organoids) [3, 6].

Despite its limitations, however, iPSC-derived organoids continue to provide an exciting frontier into expanding stem cell research within clinical settings. This leaves me wondering and looking forward to what the future of iPSC-derived organoids holds in store for us :)

[P.S this is in no way a comprehensive guide to iPSCs or organoids, but rather a glimpse into their research applications]

References

1. Cerneckis, J., Cai, H. & Shi, Y. Induced pluripotent stem cells (iPSCs): molecular mechanisms of induction and applications. Sig Transduct Target Ther 9, 112 (2024). https://doi.org/10.1038/s41392-024-01809-0

2. Liu, X., Huang, J., Chen, T. et al. Yamanaka factors critically regulate the developmental signaling network in mouse embryonic stem cells. Cell Res 18, 1177–1189 (2008). https://doi.org/10.1038/cr.2008.309

3. Xu, Ziran et al. “Merits and challenges of iPSC-derived organoids for clinical applications.” Frontiers in cell and developmental biology vol. 11 1188905. 26 May. 2023, doi:10.3389/fcell.2023.1188905

4. Sahara, Makoto. “Recent Advances in Generation of In Vitro Cardiac Organoids.” International journal of molecular sciences vol. 24,7 6244. 26 Mar. 2023, doi:10.3390/ijms24076244

5. Kim, J., Koo, BK. & Knoblich, J.A. Human organoids: model systems for human biology and medicine. Nat Rev Mol Cell Biol 21, 571–584 (2020). https://doi.org/10.1038/s41580-020-0259-3

6. Andrews, Madeline G, and Arnold R Kriegstein. “Challenges of Organoid Research.” Annual review of neurosciencevol. 45 (2022): 23-39. doi:10.1146/annurev-neuro-111020-090812