Amniotic Fluid Stem Cells: Future Perspectives

The existence of stem cells in human amniotic fluid was reported for the first time almost ten years ago. Since this discovery, the knowledge about these cells has increased dramatically. Today, amniotic fluid stem (AFS) cells are widely accepted as a new powerful tool for basic research as well as for the establishment of new stem-cell-based therapy concepts. It is possible to generate monoclonal genomically stable AFS cell lines harboring high proliferative potential without raising ethical issues. Many different groups have demonstrated that AFS cells can be differentiated into all three germ layer lineages, what is of relevance for both, the scientific and therapeutical usage of these cells. Of special importance for the latter is the fact that AFS cells are less tumorigenic than other pluripotent stem cell types. In this paper, we have summarized the current knowledge about this relatively young scientific field. Furthermore, we discuss the relevant future perspectives of this promising area of stem cell research focusing on the next important questions, which need to be answered

mTORC1 is essential for early steps during Schwann cell differentiation of amniotic fluid stem cells and regulates lipogenic gene expression.

Schwann cell development is hallmarked by the induction of a lipogenic profile. Here we used amniotic fluid stem (AFS) cells and focused on the mechanisms occurring during early steps of differentiation along the Schwann cell lineage. Therefore, we initiated Schwann cell differentiation in AFS cells and monitored as well as modulated the activity of the mechanistic target of rapamycin (mTOR) pathway, the major regulator of anabolic processes. Our results show that mTOR complex 1 (mTORC1) activity is essential for glial marker expression and expression of Sterol Regulatory Element-Binding Protein (SREBP) target genes. Moreover, SREBP target gene activation by statin treatment promoted lipogenic gene expression, induced mTORC1 activation and stimulated Schwann cell differentiation. To investigate mTORC1 downstream signaling we expressed a mutant S6K1, which subsequently induced the expression of the Schwann cell marker S100b, but did not affect lipogenic gene expression. This suggests that S6K1 dependent and independent pathways downstream of mTORC1 drive AFS cells to early Schwann cell differentiation and lipogenic gene expression. In conclusion our results propose that future strategies for peripheral nervous system regeneration will depend on ways to efficiently induce the mTORC1 pathway

Stem Cell-Induced Cell Motility: A Removable Obstacle on the Way to Safe Therapies?

Abstract It is the hope of clinicians and patients alike that stem cell-based therapeutic products will increasingly become applicable remedies for many diseases and injuries. Whereas some multipotent stem cells are already routinely used in regenerative medicine, the efficacious and safe clinical translation of pluripotent stem cells is still hampered by their inherent immunogenicity and tumorigenicity. In addition, stem cells harbor the paracrine potential to affect the behavior of cells in their microenvironment. On the one hand, this property can mediate advantageous supportive effects on the overall therapeutic concept. However, in the last years, it became evident that both, multipotent and pluripotent stem cells, are capable of inducing adjacent cells to become motile. Not only in the context of tumor development but generally, deregulated mobilization and uncontrolled navigation of patient’s cells can have deleterious consequences for the therapeutic outcome. A more comprehensive understanding of this ubiquitous stem cell feature could allow its proper clinical handling and could thereby constitute an important building block for the further development of safe therapies.</jats:p

Three-Dimensional Migration of Human Amniotic Fluid Stem Cells Involves Mesenchymal and Amoeboid Modes and is Regulated by <scp>mTORC1</scp>

Abstract Three-dimensional (3D) cell migration is an integral part of many physiologic processes. Although being well studied in the context of adult tissue homeostasis and cancer development, remarkably little is known about the invasive behavior of human stem cells. Using two different kinds of invasion assays, this study aimed at investigating and characterizing the 3D migratory capacity of human amniotic fluid stem cells (hAFSCs), a well-established fetal stem cell type. Eight hAFSC lines were found to harbor pronounced potential to penetrate basement membrane (BM)-like matrices. Morphological examination and inhibitor approaches revealed that 3D migration of hAFSCs involves both the matrix metalloprotease-dependent mesenchymal, elongated mode and the Rho-associated protein kinase-dependent amoeboid, round mode. Moreover, hAFSCs could be shown to harbor transendothelial migration capacity and to exhibit a motility-associated marker expression pattern. Finally, the potential to cross extracellular matrix was found to be induced by mTORC1-activating growth factors and reduced by blocking mTORC1 activity. Taken together, this report provides the first demonstration that human stem cells exhibit mTORC1-dependent invasive capacity and can concurrently make use of mesenchymal and amoeboid 3D cell migration modes, which represents an important step toward the full biological characterization of fetal human stem cells with relevance to both developmental research and stem cell-based therapy.</jats:p