Small Molecules, the Epigenome and Axolotl Limb Regrowth: Exploring the Complexities of Human Cell Reprogramming

Small Molecules, the Epigenome and Axolotl Limb Regrowth: Exploring the Complexities of Human Cell Reprogramming

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Research into cellular reprogramming has long been dominated by the use of intrinsic factors like transcription factors. However, new research shows that mature, human somatic cells can be reprogrammed to a pluripotent state using small molecules. Using comparative single-cell RNA-seq analysis, researchers uncovered that the chemically-induced reprogramming pathway is distinct from that induced by transcription factors.

Overview of Cellular Reprogramming

One of the seminal discoveries of modern molecular biology is that of induced pluripotent stem cells (iPSCs). Normal somatic cells, meaning all cells other than reproductive (aka germline) cells, are committed to a cell fate during development. This process involves stem cells, which have the ability to differentiate into any cell type, differentiating into one mature cell type.

In humans, the process of cellular differentiation results in cells with highly specific and restricted identities, with no ability to convert to other cell types. However, in a Nobel Prize-winning discovery, Shinya Yamanaka found that a small group of transcription factors (Yamanaka factors) could induce a mature cell back into a pluripotent stem cell state, where it could then differentiate into any number of cell types again.

The implications for improved disease modeling and the development of regenerative medicine were immediately apparent – being able to regenerate cell types using a person’s own mature cells greatly reduces the risk of adverse immune reactions. However, challenges abounded – human cells have extremely stable epigenomes, the modifications, and mechanisms that regulate gene expression, and chromatin accessibility, two of the key elements that allow for pluripotency. Thus, the efficiency of reprogramming human cells can vary widely, depending on how much ‘memory’ they retain.

Small Molecule Cellular Reprogramming

Approaches for circumventing this challenge include direct lineage reprogramming, where cells are reprogrammed between more closely related cell types. Last year, a new method was discovered that enables both direct lineage reprogramming and full cellular reprogramming to a pluripotent state using small molecules. In a paper published in Nature by Guan et al., the authors reported the ability to chemically induce somatic cells into a pluripotent state – but the underlying mechanism remained unknown.

New Analysis Uncovers the Mechanism Behind Chemical Cellular Reprogramming

In a recent paper in Cell Reports, the same research group found that the mechanism underlying their chemically-induced reprogramming is distinct from the mechanism underlying transcription factor-mediated reprogramming. 

The group drew inspiration (and comparative genomic analysis) from axolotls, a lower vertebrate that retains the ability to adaptively reprogram cells and thus has the capability to regrow limbs. The authors report that chemically-reprogrammed human cells enter an intermediate plastic state before becoming fully pluripotent again. Using single-cell RNA sequencing (scRNA-seq) of the cells as they entered this plastic state, the authors were able to reconstruct the reprogramming trajectory and identify key genes that were activated during the process. Gene ontology analysis further confirmed the upregulation of embryonic developmental genes, demonstrating a similar profile to the profile of axolotl limb regeneration.

Comparative single-cell RNA sequencing between chemically reprogrammed cells and cells with overexpressed Yamanaka factors showed that a fundamentally different process occurred in the two resultant cell types. During chemical reprogramming of the human cells, repressive methylation marks and other epigenetic features were slowly reversed, allowing the reactivation of key enhancers – however, this process could only occur when the inflammatory JNK pathway was inhibited.

Taken together, these studies indicate that chemical reprogramming uncovers a novel pathway for cellular reprogramming, increasing our understanding of the role of the epigenome during development and its modifications that can hinder cells from returning fully to a regenerative state. This is an exciting new line of research in the field of stem cells and regenerative medicine.

Outsourcing Bioinformatics Analysis: How Bridge Informatics Can Help

Groundbreaking studies like these are made possible by technological advances making biological data generation, storage, and analysis faster and more accessible than ever before. From pipeline development and software engineering to deploying existing bioinformatics tools, Bridge Informatics can help you on every step of your research journey.

As experts across data types from leading sequencing platforms, we can help you tackle the challenging computational tasks of storing, analyzing, and interpreting genomic and transcriptomic data. Bridge Informatics’ bioinformaticians are trained bench biologists, so they understand the biological questions driving your computational analysis. Click here to schedule a free introductory call with a member of our team.

Jane Cook, Biochemist & Content Writer, Bridge Informatics

Jane Cook, the leading Content Writer for Bridge Informatics, has written over 100 articles on the latest topics and trends for the bioinformatics community. Jane’s broad and deep interdisciplinary molecular biology experience spans developing biochemistry assays to genomics. Prior to joining Bridge, Jane held research assistant roles in biochemistry research labs across a variety of therapeutic areas. While obtaining her B.A. in Biochemistry from Trinity College in Dublin, Ireland, Jane also studied journalism at New York University’s Arthur L. Carter Journalism Institute. As a native Texan, she embraces any challenge that comes her way. Jane hails from Dallas but returns to Ireland any and every chance she gets. If you’re interested in reaching out, please email [email protected] or [email protected].

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