Research Paper Volume 13, Issue 24 pp 25739—25762

Small molecules for cell reprogramming: a systems biology analysis

Anna Knyazer1, *, , Gabriela Bunu2, *, , Dmitri Toren2, , Teodora Bucaciuc Mracica2, , Yael Segev1, , Marina Wolfson1, , Khachik K. Muradian3, , Robi Tacutu2, , Vadim E. Fraifeld1,3, ,

  • 1 The Shraga Segal Department of Microbiology, Immunology and Genetics, Center for Multidisciplinary Research on Aging, Ben-Gurion University of the Negev, Beer-Sheva, Israel
  • 2 Systems Biology of Aging Group, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
  • 3 D.F. Chebotarev Institute of Gerontology of National Academy of Medical Sciences of Ukraine, Kiev, Ukraine
* Equal contribution

Received: August 6, 2021       Accepted: November 24, 2021       Published: December 17, 2021
How to Cite

Copyright: © 2021 Knyazer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


If somatic stem cells would be able to maintain their regenerative capacity over time, this might, to a great extent, resolve rejuvenation issues. Unfortunately, the pool of somatic stem cells is limited, and they undergo cell aging with a consequent loss of functionality. During the last decade, low molecular weight compounds that are able to induce or enhance cell reprogramming have been reported. They were named “Small Molecules” (SMs) and might present definite advantages compared to the exogenous introduction of stemness-related transcription factors (e.g. Yamanaka’s factors). Here, we undertook a systemic analysis of SMs and their potential gene targets. Data mining and curation lead to the identification of 92 SMs. The SM targets fall into three major functional categories: epigenetics, cell signaling, and metabolic “switchers”. All these categories appear to be required in each SM cocktail to induce cell reprogramming. Remarkably, many enriched pathways of SM targets are related to aging, longevity, and age-related diseases, thus connecting them with cell reprogramming. The network analysis indicates that SM targets are highly interconnected and form protein-protein networks of a scale-free topology. The extremely high contribution of hubs to network connectivity suggests that (i) cell reprogramming may require SM targets to act cooperatively, and (ii) their network organization might ensure robustness by resistance to random failures. All in all, further investigation of SMs and their relationship with longevity regulators will be helpful for developing optimal SM cocktails for cell reprogramming with a perspective for rejuvenation and life span extension.


2-Me-5HT: 2-methyl-5-hydroxytryptamine; 8-Br-cAMP: Bromoadenosine 3′, 5′-cyclic monophosphate; BrdU: Bromodeoxyuridine; CS: Cellular senescence; D2–5-HT2A: Dopamine D2 and serotonin 5-HT2A receptors; DARPP-32: Dopamine- and cAMP-regulated phosphoprotein; DNMT: DNA methyltransferase; DZNep: 3-Deazaneplanocin A; EGCG: Epigallocatechin-3-Gallate; ESCs: Embryonic stem cells; EZH: Enhancer of Zeste Homologue; Fru-2,6-P2: Fructose 2,6-bisphosphate; GSK3: Glycogen synthase kinase 3; HDAC: Histone deacetylase; HIF: Hypoxia-inducible factor-1; Hif1alpha: Hypoxia-inducible factor 1 alpha; HMDB: Human Metabolome Database; HMT: Histone methyltransferase; IBMX: 3-Isobutyl-1-Methylxanthine; iP: Induced pluripotency; LAGs: Longevity-associated genes; MW: Molecular weight; O4I3: OCT4-inducing compound 3; OSKM: Oct3/4, Sox2, Klf4, and c-Myc (Yamanaka's factors); PDK1: 3′-phosphoinositide-dependent kinase-1; PFK-1: Phosphofructokinase 1; PI3K: Phosphoinositide 3-kinase; PPIs: Protein-protein interactions; ROS: Reactive oxygen species; SAH: S-Adenosyl-l-homocysteine; SAHA: Suberoylanilide hydroxamic acid; SMs: Small molecules; TFs: Transcription factors.