IGF2BP1 Expression in Human Mesenchymal Stem Cells Significantly Affects Their Proliferation and Is Under the Epigenetic Control of TET1/2 Demethylases

Abstract

Mesenchymal stem cells (MSCs) are a population of cells harboring in many tissues with the ability to differentiate toward many different lineages. Unraveling the molecular profile of MSCs is of great importance due to the fact that these cells are very often used in preclinical and clinical studies. We have previously reported the expression of insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) an oncofetal mRNA-binding protein-in different stem cell types such as bone marrow (BM)-MSC and umbilical cord blood (UCB)-hematopoietic stem cells. Here, we demonstrate that MSCs of adipose tissue, BM, and UC origin have a differential pattern of IGF2BP1 and ten-eleven-translocate 1/2 (TET1/2) expression that could correlate with their proliferation potential. Upon IGF2BP1 interference, a significant reduction of cell proliferation is observed, accompanied by reduced expression of c-MYC and GLI1 and increased p21. We also present, for the first time, evidence that IGF2BP1 is epigenetically regulated by TET1 and TET2 demethylases. Specifically, we show that TET1 directly binds to the promoter of IGF2BP1 gene and affects the hydroxymethylation status of its promoter. These results indicate that IGF2BP1 and TET1/2 contribute to the stemness of MSCs, at least regarding their proliferative potential.

MicroRNA and mRNA cargo of extracellular vesicles from porcine adipose tissue-derived mesenchymal stem cells

“…Finally, let-7f, also upregulated in EVs, targets genes associated to transcription and membrane-associated proteins with implications in cellular reprogramming and growth, like the upregulated lin-28 homolog-B (LIN28B) 59 , high-mobility-group AT-hook-2 (HMGA2) 60 , and the insulin-like growth factor-2 mRNA binding protein-1 (IGF2BP1) 61 . Collectively, our observations suggest that EVs are potential modulators of tissue repair by reprogramming target cells.…”

Integrated transcriptomic and proteomic analysis of the molecular cargo of extracellular vesicles derived from porcine adipose tissue-derived mesenchymal stem cells

“…miRNAs are small non-coding RNA molecules that act as post-transcriptional negative regulators through base-pairing interactions with their targets mRNAs, leading to their degradation or translational repression. Among overlapping EV-enriched mRNAs and miRNA target genes are Serine/Threonine Kinase-17b (STK17B) and Tet Methylcytosine Dioxygenase-2 (TET2), which modulate MSC proliferation [37, 38], and RPTOR Independent Companion Of MTOR Complex-2 (RICTOR), an adaptor protein of the mammalian target of rapamycin (mTOR) multiprotein complex-2 that modulates MSC differentiation [39]. Therefore, EV miRNA-induced posttranscriptional regulation of these genes may be one of the mechanisms by which MSCs regulate their neighbors’ proliferation and differentiation.…”

The effect of extended passaging on the phenotype and osteogenic potential of human umbilical cord mesenchymal stem cells

“…These cells can differentiate into adipocytes, osteoblasts, chondrocytes, neurons, and endothelial cells [15][16][17][18][19][20][21][22][23][24]. The use of hUCMSCs poses several major advantages: (1) Umbilical cords are medical waste discarded after birth and can therefore be collected at a low cost; (2) Because many babies are born each year, hUCMSCs are a virtually inexhaustible stem cell source; (3) hUCMSCs can be collected non-invasively, unlike the harvesting procedure required for BMSCs; (4) hUCMSCs can be collected without the ethical controversies surrounding human embryonic stem cells (hESCs); (5) hUCMSCs are a primitive MSC population that exhibit a high degree of plasticity and developmental flexibility; and (6) hUCMSCs thus do not appear to cause immune-rejection responses in vivo [16,[19][20][21][25][26][27][28][29].…”