Human Endogenous Retrovirus-H and K Expression in Human Mesenchymal Stem Cells as Potential Markers of Stemness

Abstract

Objective: The human endogenous retroviruses (HERVs) are endogenous retroviruses that were inserted into the germ cell DNA of humans over 30 million years ago. Insertion of HERVs into the chromosomal DNA can influence a number of host genes in various modes during human evolution and their proviral long terminal repeats can participate in the transcriptional regulation of various cellular genes. Our aim was to evaluate the pol gene expression of HERV-K and HERV-H in mesenchymal stem cells (MSCs) in relation with the expression of stemness genes such as NANOG, OCT-4, and SOX-2. Methods: MSCs were isolated from bone marrow of healthy donors and expanded until the 5th passage in α-MEM with 10% fetal bovine serum. HERV-K, HERV-H pol gene, NANOG, OCT-4, SOX-2, and GAPDH expression was quantified by real-time PCR in MSCs during the expansion. Results: HERV-K and HERV-H expression was always higher at p1 compared to other passages and this difference reached a high statistical significance when passage p1 was compared with passage 3. In addition, NANOG, OCT-4, and SOX-2 expression at p1 was significantly higher than their expression at p3. Pearson’s test demonstrated a strong correlation between the expression of HERV-K and HERV-H and the expression of NANOG, OCT-4, and SOX-2. Conclusions: Our findings showed that HERV-K and H were concurrently expressed with pluripotency biomarkers NANOG, OCT-4, and SOX-2.

Regulation of stem cell function and neuronal differentiation by HERV-K via mTOR pathway

“…Only type 2 has an intact env gene (9). HML-2 activation has been observed in pluripotent stem cells (PSC) (10) and mesenchymal stem cells (11). Unregulated expression has been found in certain tumors (12) and overexpression in postmitotic neurons can cause neurodegeneration (13).…”

Retroviral Elements in Human Evolution and Neural Development

“…Recently acquired HERV-K subfamily HML-2 has nearly full-length viral sequences with open reading frames for gag, pro, pol, and env genes [23]. HML-2 activation has been observed in pluripotent stem cells [24], mesenchymal stem cells [25] and certain tumors [26]. We found that HML-2 envelope expression increased in pluripotent stem cells but diminished during neuronal differentiation [16].…”

Overexpression of Endogenous Retroviruses and Malignancy Markers in Neuroblastoma Cell Lines by Medium-Induced Microenvironmental Changes

“…Our results suggest a strong correlation of HERV-K GAG with stressful cell culture conditions by serumdepleted stem cell medium in all three NB cell lines (Figure 1). In this context, studies on human pluripotent stem cells (PSCs) suggest HERV-K (HML-2) activation in early stem cell development (51,52) and that the differentiation of PSCs into neuronal cells is promoted by silencing of its ENV (53). It is of particular interest, that Wang's group were not able to demonstrate similar results with GAG proteins.…”