scispace - formally typeset
Search or ask a question
Author

Kira Schichel

Bio: Kira Schichel is an academic researcher from University of Düsseldorf. The author has contributed to research in topics: Telomere & Progenitor cell. The author has co-authored 1 publications.

Papers
More filters
Journal ArticleDOI
TL;DR: In this paper, the authors focused on the activity of the ENV protein and investigated how it can be neutralized for an improved remyelination in the context of multiple sclerosis.
Abstract: Myelin repair in the adult central nervous system (CNS) is driven by successful differentiation of resident oligodendroglial precursor cells (OPCs) and thus constitutes a neuroregenerative process capable to compensate for functional deficits upon loss of oligodendrocytes and myelin sheaths as it is observed in multiple sclerosis (MS). The human endogenous retrovirus type W (HERV-W) represents a MS specific pathogenic entity and its envelope (ENV) protein was previously identified as negative regulator of OPC maturation – hence of relevance in the context of diminished myelin repair. We here focused on the activity of the ENV protein and investigated how it can be neutralized for an improved remyelination. ENV mediated activation of TLR4 increases inducible nitric oxide synthase (iNOS) expression, prompts nitrosative stress and results in myelin-associated deficits including decreased levels of oligodendroglial maturation marker expression and morphological alterations. Intervention of TLR4 surface expression represents a potential means to rescue such ENV dependent deficits. To this end, the rescue capacity of specific substances, either modulating V-ATPase activity or myeloid differentiation 2 (MD2) mediated TLR4 glycosylation status, such as compound 20 (C20), L48H437 or folimycin were analyzed, as these processes were demonstrated to be relevant for TLR4 surface expression. We found that pharmacological treatment can rescue the maturation arrest of oligodendroglial cells and their myelination capacity, and can prevent iNOS induction in the presence of the ENV protein. In addition, downregulation of TLR4 surface expression was observed. Furthermore, mitochondrial integrity crucial for oligodendroglial cell differentiation was affected in the presence of ENV and ameliorated upon pharmacological treatment. Our study therefore provides novel insights into possible means to overcome myelination deficits associated with HERV-W ENV mediated myelin deficits.

5 citations

Journal ArticleDOI
17 Jan 2023-Cells
TL;DR: In this article , a human podocyte progenitor cell line was derived from the urine of a 51-year-old male and the primary cells were cultured over the course of one year with high proliferation capacity and P53 expression.
Abstract: Recent demographic studies predict there will be a considerable increase in the number of elderly people within the next few decades. Aging has been recognized as one of the main risk factors for the world’s most prevalent diseases such as neurodegenerative disorders, cancer, cardiovascular disease, and metabolic diseases. During the process of aging, a gradual loss of tissue volume and organ function is observed, which is partially caused by replicative senescence. The capacity of cellular proliferation and replicative senescence is tightly regulated by their telomere length. When telomere length is critically shortened with progressive cell division, cells become proliferatively arrested, and DNA damage response and cellular senescence are triggered, whereupon the “Hayflick limit” is attained at this stage. Podocytes are a cell type found in the kidney glomerulus where they have major roles in blood filtration. Mature podocytes are terminal differentiated cells that are unable to undergo cell division in vivo. For this reason, the establishment of primary podocyte cell cultures has been very challenging. In our present study, we present the successful immortalization of a human podocyte progenitor cell line, of which the primary cells were isolated directly from the urine of a 51-year-old male. The immortalized cell line was cultured over the course of one year (~100 passages) with high proliferation capacity, endowed with contact inhibition and P53 expression. Furthermore, by immunofluorescence-based expression and quantitative real-time PCR for the podocyte markers CD2AP, LMX1B, NPHS1, SYNPO and WT1, we confirmed the differentiation capacity of the immortalized cells. Finally, we evaluated and confirmed the responsiveness of the immortalized cells on the main mediator angiotensin II (ANGII) of the renin–angiotensin system (RAAS). In conclusion, we have shown that it is possible to bypass cellular replicative senescence (Hayflick limit) by TERT-driven immortalization of human urine-derived pre-podocyte cells from a 51-year-old African male.

2 citations

Posted ContentDOI
23 May 2022-bioRxiv
TL;DR: It is shown that it is possible to by-pass cellular replicative senescence (Hayflick limit) by TERT-driven immortalization of human urine-derived pre-podocyte cells from a 51-year-old African male.
Abstract: Recent demographic studies predict there will be a considerable increase of elderly people within the next decades. Aging has been recognized as one of the main risk factors of the world’s most prevalent diseases, including neurodegenerative disorders, cancer, cardiovascular disease, and metabolic disease. During the process of aging a gradual loss of tissue volume and organ function is observed, which is partially caused by replicative senescence. The capacity of cellular proliferation and replicative senescence is tightly regulated by their telomere length. When the telomere length with progressive cell division is critically shortened, the cell becomes proliferative arrested and DNA damage response and cellular senescence are triggered. At this time point the so called “Hayflick limit” is attained. Podocytes are a cell type that is found in the kidney glomerulus where they have major implications in blood filtration. Mature podocytes are terminal differentiated cells that are unable to undergo cell division in vivo. For this reason, the establishment of podocyte cell cultures has been very challenging. In our present study, we present the successful immortalization of a human podocyte progenitor cell line, of which the primary cell cells were isolated directly from the urine of a 51-year-old male. The immortalized cell line has been cultured over the course of one year (∼100 passages) with high proliferation capacity, while still endowed with contact inhibition and P53 expression and activation. Furthermore, by immunofluorescent-based expression and quantitative Real-Time PCR for the podocyte markers NPHS1, SYNPO and WT1 we confirmed the differentiation capacity of the immortalized cells. Finally, we evaluated and confirmed the responsiveness of the immortalized cells on the main mediator Angiotensin II (ANGII) of the renin-angiotensin-system (RAS). Elevated levels of ANGII have been identified as a main risk factor for the initiation and progression of chronic kidney disease (CKD). CKD is characterized by an impairment of podocyte function and subsequently podocyte apoptosis. As a major risk factor for patients to develop CKD, diabetes, hypertension, heart disease and stroke have been recognized - all of which show increased incidence in elderly people. In conclusion, we have shown that it is possible to by-pass cellular replicative senescence (Hayflicks limit) by TERT-driven immortalization of human urine-derived pre-podocyte cells from a 51-year-old African male.

2 citations


Cited by
More filters
Journal ArticleDOI
TL;DR: Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) with a well-documented role in the innate and adaptive immune responses as mentioned in this paper , and their activation has also been linked to several brain functions including neurogenesis and synaptogenesis.

4 citations

Journal ArticleDOI
TL;DR: In this article , the authors discuss the implications of HERVs in all four contexts in relation to innate immunity and their association with various pathological disease states, including traumatic, toxic, or infection-related stress, leading to a buildup of viral transcripts.
Abstract: Endogenous retroviruses (ERVs), or LTR retrotransposons, are a class of transposable elements that are highly represented in mammalian genomes. Human ERVs (HERVs) make up roughly 8.3% of the genome and over the course of evolution, HERV elements underwent positive selection and accrued mutations that rendered them non-infectious; thereby, the genome could co-opt them into constructive roles with important biological functions. In the past two decades, with the help of advances in sequencing technology, ERVs are increasingly considered to be important components of the innate immune response. While typically silenced, expression of HERVs can be induced in response to traumatic, toxic, or infection-related stress, leading to a buildup of viral transcripts and under certain circumstances, proteins, including functionally active reverse transcriptase and viral envelopes. The biological activity of HERVs in the context of the innate immune response can be based on the functional effect of four major viral components: (1) HERV LTRs, (2) HERV-derived RNAs, (3) HERV-derived RNA:DNA duplexes and cDNA, and (4) HERV-derived proteins and ribonucleoprotein complexes. In this review, we will discuss the implications of HERVs in all four contexts in relation to innate immunity and their association with various pathological disease states.

3 citations

Journal ArticleDOI
TL;DR: In this article , the authors discuss the bidirectional relationship between ERV expression and inflammation and highlight that numerous entry points to this reciprocal sequence of events exist, including initial infections with ERVactivating pathogens, exposure to non-infectious inflammatory stimuli, and conditions in which epigenetic silencing of ERV elements is disrupted.
Abstract: Human endogenous retroviruses (ERVs) are ancestorial retroviral elements that were integrated into our genome through germline infections and insertions during evolution. They have repeatedly been implicated in the aetiology and pathophysiology of numerous human disorders, particularly in those that affect the central nervous system. In addition to the known association of ERVs with multiple sclerosis and amyotrophic lateral sclerosis, a growing number of studies links the induction and expression of these retroviral elements with the onset and severity of neurodevelopmental and psychiatric disorders. Although these disorders differ in terms of overall disease pathology and causalities, a certain degree of (subclinical) chronic inflammation can be identified in all of them. Based on these commonalities, we discuss the bidirectional relationship between ERV expression and inflammation and highlight that numerous entry points to this reciprocal sequence of events exist, including initial infections with ERV-activating pathogens, exposure to non-infectious inflammatory stimuli, and conditions in which epigenetic silencing of ERV elements is disrupted.

1 citations

Journal ArticleDOI
TL;DR: This review collects studies of the interaction between HERV elements and Toll-like receptors and attempts to provide an overview of their role in the immunopathological mechanisms of inflammatory and autoimmune diseases.
Abstract: Human endogenous retroviruses (HERVs) are estimated to comprise ∼8% of the entire human genome, but the vast majority of them remain transcriptionally silent in most normal tissues due to accumulated mutations. However, HERVs can be frequently activated and detected in various tissues under certain conditions. Nucleic acids or proteins produced by HERVs can bind to pattern recognition receptors of immune cells or other cells and initiate an innate immune response, which may be involved in some pathogenesis of diseases, especially cancer and autoimmune diseases. In this review, we collect studies of the interaction between HERV elements and Toll-like receptors and attempt to provide an overview of their role in the immunopathological mechanisms of inflammatory and autoimmune diseases.

1 citations

Posted ContentDOI
23 Jan 2023-bioRxiv
TL;DR: In this paper , the secretome of urine of an acute kidney injury (AKI) patient cohort employing a kidney-biomarker cytokine assay was analyzed and it was shown that cytokines in the urine of AKI patients trigger processes which are needed to repair the damaged nephron and activate TP53 and SIRT1.
Abstract: Acute kidney injury (AKI) is a major kidney disease with a poor clinical outcome. It is a common complication with an incidence of 10-15% of patients admitted to hospital. This rate even increases for patients who are admitted to the intensive care unit with an incidence of >50%. AKI is characterized by a rapid increase in serum creatinine, decrease in urine output, or both. Associated Symptoms include feeling sick or being sick, diarrhoea, dehydration, decreased urine output-although occasionally urine output remains normal, fluid retention-causing swelling in the legs or ankles, shortness of breath, fatigue and nausea. However, sometimes acute kidney injury causes no signs or symptoms and is detected by lab tests. Therefore, an urgent demand for non-invasive biomarkers for early detection of AKI are highly desirable. This might enable the prevention of the progression from AKI to CKD. In this study, we analysed the secretome of urine of an AKI patient cohort employing a kidney-biomarker cytokine assay. Based on these results we suggest, ADIPOQ, EGF and SERPIN3A as potential biomarkers, which might be able to detect AKI as soon as 24 h post-surgery. For the later stages, common biomarkers for the detection of AKI in both male and female patients we suggest, VEGF, SERPIN3A, TNFSF12, ANPEP, CXCL1, REN, CLU and PLAU. These markers in combination might present a robust strategy to identify the development of AKI as early as 24h or 72h post-surgery. Furthermore, we evaluated the effect of patient and healthy urine on human podocyte cells. We conclude that cytokines in the urine of AKI patients trigger processes which are needed to repair the damaged nephron and activate TP53 and SIRT1 to maintain the balance between proliferation, angiogenesis, and cell cycle arrest. In conclusion, the Renin-Angiotensin pathway seems to have major implications.