Next-generation direct reprogramming

Riya Keshri; Damien Detraux; Ashish Phal; Clara McCurdy; Samriddhi Jhajharia; Tung Ching Chan; Julie Mathieu; Hannele Ruohola-Baker

doi:10.3389/fcell.2024.1343106

Next-generation direct reprogramming

Front Cell Dev Biol. 2024 Feb 2:12:1343106. doi: 10.3389/fcell.2024.1343106. eCollection 2024.

Authors

Riya Keshri^#^{1

2}, Damien Detraux^#^{1

2}, Ashish Phal^#^{1

2

3}, Clara McCurdy^{1

2

4}, Samriddhi Jhajharia^{1

2}, Tung Ching Chan^{1

2}, Julie Mathieu^{2

5}, Hannele Ruohola-Baker^{1

2

3}

Affiliations

¹ Department of Biochemistry, School of Medicine, University of Washington, Seattle, WA, United States.
² Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA, United States.
³ Department of Bioengineering, College of Engineering, University of Washington, Seattle, WA, United States.
⁴ Institute for Protein Design, University of Washington, Seattle, WA, United States.
⁵ Department of Comparative Medicine, School of Medicine, University of Washington, Seattle, WA, United States.

^# Contributed equally.

Abstract

Tissue repair is significantly compromised in the aging human body resulting in critical disease conditions (such as myocardial infarction or Alzheimer's disease) and imposing a tremendous burden on global health. Reprogramming approaches (partial or direct reprogramming) are considered fruitful in addressing this unmet medical need. However, the efficacy, cellular maturity and specific targeting are still major challenges of direct reprogramming. Here we describe novel approaches in direct reprogramming that address these challenges. Extracellular signaling pathways (Receptor tyrosine kinases, RTK and Receptor Serine/Theronine Kinase, RSTK) and epigenetic marks remain central in rewiring the cellular program to determine the cell fate. We propose that modern protein design technologies (AI-designed minibinders regulating RTKs/RSTK, epigenetic enzymes, or pioneer factors) have potential to solve the aforementioned challenges. An efficient transdifferentiation/direct reprogramming may in the future provide molecular strategies to collectively reduce aging, fibrosis, and degenerative diseases.

Keywords: aging; cardiac muscles; direct reprogramming; partial reprogramming; pioneer factors; signaling; skeletal muscle; transdifferentiation.

Publication types

Review

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was partially supported by R01DE033016 for JM and HR-B.