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Project
Characterization of the in vivo generated hepatic progeny from adult human skin-derived precursor cells and evaluation of their potential use for in vitro safetyscreening of pharmaceuticals and liver disease. (FWOTM647)
Hepatocytes in the liver represent the central place where pharmaceuticals are biotransformed.
They are as such highly susceptible to toxicity leading to so-called Drug Induced Liver Injury (DILI). Currently, DILI is a major cause for drug attrition, demonstrating that the available models for assessing liver toxicity are not performing adequately. Hence, the pharmaceutical industry urgently needs novel, preferably in vitro test systems that are more suitable to predict adverse liver responses in humans. Since primary human hepatocytes are very scarce, other
sources such as stem cells, with the ability for self-renewal and potential for multi-lineage differentiation, need to be explored. Here, human skin-derived precursors (hSKPs) are proposed. Indeed, as shown during the predoctoral research of the applicant, this stem cell population (i) is easily and reproducibly isolated from postnatal human skin, (ii) can be differentiated in vitro into hepatocyte-like cells and (iii) bears valuable immunomodulatory and -suppressive properties, making them not only interesting for reliable safety screening of
pharmaceuticals, but in particular also for potential therapeutical applications. Therefore, in the current postdoctoral project, the in vivo migration and hepatic differentiation properties of the hSKPs will be investigated using an appropriate mouse model. It will be determined whether the so-generated human hepatocyte-like cells have potentiality for in vitro drug safety screening. Furthermore, by evaluating their immunological properties during differentiation and the effects of hSKPs transplanted in an end-stage liver disease mouse model, their potential for further clinical applicability will be explored.
They are as such highly susceptible to toxicity leading to so-called Drug Induced Liver Injury (DILI). Currently, DILI is a major cause for drug attrition, demonstrating that the available models for assessing liver toxicity are not performing adequately. Hence, the pharmaceutical industry urgently needs novel, preferably in vitro test systems that are more suitable to predict adverse liver responses in humans. Since primary human hepatocytes are very scarce, other
sources such as stem cells, with the ability for self-renewal and potential for multi-lineage differentiation, need to be explored. Here, human skin-derived precursors (hSKPs) are proposed. Indeed, as shown during the predoctoral research of the applicant, this stem cell population (i) is easily and reproducibly isolated from postnatal human skin, (ii) can be differentiated in vitro into hepatocyte-like cells and (iii) bears valuable immunomodulatory and -suppressive properties, making them not only interesting for reliable safety screening of
pharmaceuticals, but in particular also for potential therapeutical applications. Therefore, in the current postdoctoral project, the in vivo migration and hepatic differentiation properties of the hSKPs will be investigated using an appropriate mouse model. It will be determined whether the so-generated human hepatocyte-like cells have potentiality for in vitro drug safety screening. Furthermore, by evaluating their immunological properties during differentiation and the effects of hSKPs transplanted in an end-stage liver disease mouse model, their potential for further clinical applicability will be explored.
Date:1 Oct 2012 → 1 Oct 2017
Keywords:Cultures And Co-Cultures, Apoptosis, Hepatocytes, apoptosis, Isobutene, Cosmetics, Toxicity, Saponins, Dermato-Cosmetics, Anti-Epileptic Drugs, Phytochemistry, Drug Metabolism, Dermato-Cosmetic Sciences, In Vitro Toxicology, Liver Cells, Pharmacognosy, Human Skin, Keratinocytes
Disciplines:Pharmacognosy and phytochemistry, Morphological sciences, Dermatology