Small Molecules in Cellular Reprogramming and Differentiation

Abstract Mammals have a limited capacity to regenerate their tissues and organs. One of the mechanisms associated with natural regeneration is dedifferentiation. Several small molecules such as vitamin C and growth factors could improve reprogramming efficiency. In this study, the NTERA2-D1 (NT2) cells were induced towards differentiation (NT2-RA) with 10-5 M retinoic acid (RA) for three days and then subjected to various amounts of vitreous humor (VH). Results show that the growth rate of these cells was reduced, while this rate was partly restored upon treatment with VH (NT2-RA-VH). Cell cycle analysis with PI method also showed that the numbers of cells at the S phase of the cell cycle in these cells were increased. The levels of SSEA3 and TRA-1-81 antigens in NT2-RA were dropped but they increased in NT2- RA-VH to a level similar to the NT2 cells. The level of SSEA1 had an opposite pattern. Expression of OCT4 gene dropped after RA treatment, but it was recovered in NT2-RA-VH cells. In conclusion, we suggest VH as a potent mixture for improving the cellular reprogramming leading to dedifferentiation.

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Advances in small molecules in cellular reprogramming: effects, structures, and mechanisms

Current Stem Cell Research & Therapy ◽

10.2174/1574888x15666200621172042 ◽

2020 ◽

Vol 15 ◽

Author(s):

Jun Zeng ◽

Yanjiao Li ◽

Zhaoxia Ma ◽

Min Hu

Keyword(s):

Small Molecules ◽

Active Sites ◽

Transforming Growth Factor ◽

Glycogen Synthase ◽

Epigenetic Modification ◽

Somatic Cells ◽

Embryonic Stem ◽

Cellular Reprogramming ◽

Signal Modulation ◽

Metabolic Modulation

: The method of cellular reprogramming using small molecules involves manipulation of somatic cells to generate desired cell types under chemically limited conditions, thus avoiding the ethical controversy of embryonic stem cells and the potential hazards of gene manipulation. The combinations of small molecules and their effects on mouse and human somatic cells are similar. Several small molecules, including CHIR99021, 616452, A83-01, SB431542, forskolin, tranylcypromine and valproic acid [VPA], have been frequently used in reprogramming of mouse and human somatic cells. This indicated that the reprogramming approaches related to these compounds were essential. These approaches were mainly divided into four classes: epigenetic modification, signal modulation, metabolic modulation and senescent suppression. The structures and functions of small molecules involved in these reprogramming approaches have been studied extensively. Molecular docking gave insights into the mechanisms and structural specificities of various small molecules in the epigenetic modification. The binding modes of RG108, Bix01294, tranylcypromine and VPA with their corresponding proteins clearly illustrated the interactions between these compounds and the active sites of the proteins. Glycogen synthase kinase 3β [CHIR99021], transforming growth factor β [616452, A83-01 and SB431542] and protein kinase A [forskolin] signaling pathway play important roles in signal modulation during reprogramming, however, the mechanisms and structural specificities of these inhibitors are still unknown. Further, the number of small molecules in the approaches of metabolic modulation and senescent suppression were too few to compare. This review aims to serve as a reference for reprogramming through small molecules and benefit future regenerative medicine and clinical drug discovery.

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Effects of the Extracts from Fruit and Stem of Camellia japonica on Induced Pluripotency and Wound Healing

Journal of Clinical Medicine ◽

10.3390/jcm7110449 ◽

2018 ◽

Vol 7 (11) ◽

pp. 449 ◽

Cited By ~ 4

Author(s):

Hyejin Jeon ◽

Jae Kim ◽

Jung‐Kyun Choi ◽

Enna Han ◽

Cho-Lok Song ◽

...

Keyword(s):

Wound Healing ◽

Stem Cell ◽

Small Molecules ◽

Plant Extracts ◽

Induced Pluripotent Stem Cell ◽

Cellular Reprogramming ◽

Camellia Japonica ◽

Natural Plant ◽

Ipsc Generation

Small molecules that improve reprogramming, stem cell properties, and regeneration can be widely applied in regenerative medicine. Natural plant extracts represent an abundant and valuable source of bioactive small molecules for drug discovery. Natural products themselves or direct derivatives of them have continued to provide small molecules that have entered clinical trials, such as anticancer and antimicrobial drugs. Here, we tested 3695 extracts from native plants to examine whether they can improve induced pluripotent stem cell (iPSC) generation using genetically homogeneous secondary mouse embryonic fibroblasts (MEFs) harboring doxycycline (dox)-inducible reprograming transgenes. Among the tested extracts, extracts from the fruit and stem of Camellia japonica (CJ) enhanced mouse and human iPSC generation and promoted efficient wound healing in an in vivo mouse wound model. CJ is one of the best-known species of the genus Camellia that belongs to the Theaceae family. Our findings identified the natural plant extracts from the fruit and stem of CJ as novel regulators capable of enhancing cellular reprogramming and wound healing, providing a useful supplement in the development of a more efficient and safer method to produce clinical-grade iPSCs and therapeutics.

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Gap junctions in the prothoracic glands of the tobacco hornworm, Manduca sexta

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100123933 ◽

1992 ◽

Vol 50 (1) ◽

pp. 706-707

Author(s):

Ji-da Dai ◽

M. Joseph Costello ◽

Lawrence I. Gilbert

Keyword(s):

Gap Junctions ◽

Small Molecules ◽

Manduca Sexta ◽

Freeze Fracture ◽

Cell Communication ◽

Cellular Level ◽

Thin Sections ◽

Prothoracic Glands ◽

Polyhydroxylated Steroids ◽

Stimulation Of

Insect molting and metamorphosis are elicited by a class of polyhydroxylated steroids, ecdysteroids, that originate in the prothoracic glands (PGs). Prothoracicotropic hormone stimulation of steroidogenesis by the PGs at the cellular level involves both calcium and cAMP. Cell-to-cell communication mediated by gap junctions may play a key role in regulating signal transduction by controlling the transmission of small molecules and ions between adjacent cells. This is the first report of gap junctions in the PGs, the evidence obtained by means of SEM, thin sections and freeze-fracture replicas.

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Fusion and Fission Processes in Exocytosis: Possible Roles for Synexin and Osmotic Lysis in the Two Events

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s1431927600002634 ◽

1980 ◽

Vol 38 ◽

pp. 594-597

Author(s):

H.B. Pollard ◽

C.E. Creutz ◽

C.J. Pazoles ◽

J.H. Scott

Keyword(s):

Small Molecules ◽

Chromaffin Cells ◽

Adrenal Glands ◽

General Concept ◽

Extracellular Calcium ◽

Large Protein ◽

Granule Membrane ◽

Osmotic Lysis ◽

Per Se ◽

Chemical Evidence

Exocytosis is a general concept describing secretion of enzymes, hormones and transmitters that are otherwise sequestered in intracellular granules. Chemical evidence for this concept was first gathered from studies on chromaffin cells in perfused adrenal glands, in which it was found that granule contents, including both large protein and small molecules such as adrenaline and ATP, were released together while the granule membrane was retained in the cell. A number of exhaustive reviews of this early work have been published and are summarized in Reference 1. The critical experiments demonstrating the importance of extracellular calcium for exocytosis per se were also first performed in this system (2,3), further indicating the substantial service given by chromaffin cells to those interested in secretory phenomena over the years.

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