Genetically modified human stem cell
Main foci of our research are two major bottlenecks that currently hinder the routine use of stem cells for regenerative therapies. Firstly, ex vivo proliferative expansion of stem cells is a limiting factor and has proven extremely difficult. Biomaterial-based approaches will be explored for their potential to overcome stem cell scarcity (=> Biomaterials and stem cell proliferation). Secondly, engineering of these cells has been frustratingly elusive, preventing their modification for improved therapeutic efficacy (=> Genetic engineering of stem cells).
Lastly, we envisage combining elements of both technological approaches in a translational research project revolving around the “foreign body reaction - FBR” (=> Innate immunity and FBR). Here, the use of engineered animal models complemented by in vitro experiments employing differentiated stem cells as well as immune cell types is expected to deliver fundamental insights in the FBR, which currently thwarts many otherwise promising developments in implant technology and biomaterial based therapies.
Biomaterials and stem cell proliferation
Stem cell on biomaterial
The multiplication of stem cells for the use in the clinic is by and large an unmet medical need. This is in particular true for hematopoietic stem cells (HSC), the only stem cell type having a long standing, proven track record in successful stem cell transplantation.
Practical solutions to that problem face two main challenges: (1) HSC proliferation to yield cell numbers high enough for specific applications, and (2) to do so in a manner guaranteeing that the phenotype of the cells remains unaltered, i. e. preservation of true stem cell capacity to reconstitute the entire blood/ immune system.
To meet both quantitative and qualitative criteria, our research focuses on the establishment of controlled and reproducible stem cell culture conditions by novel synthetic biocompatible materials and chemically defined artificial extracellular matrix (ECM) components. Of particular interest is the creation of artificial stem cell niches that foster HSC maintenance and expansion in tissue culture for the benefit of human stem cell transplantation.
Genetic engineering of stem cells
Research on stem cells is closely linked to genetic engineering technology. Obvious examples are gene corrections and additive gene transfer in engineered cell therapy, the facilitation of cell tracing and selection, both in vivo and in vitro, or the provision of cells that are altered such that they can constitute or contribute to preclinical disease and screening models. Their proliferation and differentiation potential renders stem cell logical targets for genetic engineering.
Once a defined genetic alteration has been introduced and validated (chromosome engineering), cells can be expanded and differentiated in various cell types. So far, however, several stem cell types can only proliferate in their natural environment. Others though, in particular induced pluripotent stem cells (iPSC), can be propagated in vitro, allowing even clonal outgrowth. These properties make iPSC immediate targets for the engineering of personalized or disease specific cellular model systems.
A main application will be the study of cellular interactions with the environment under both physiological and pathophysiological conditions. The elucidation and steering of interactions of these engineered cells - with other cells, tissue matrices, or with biomaterials - will be central to our approach to support regeneration and healing.
Innate immunity and FBR
The innate immune system is the evolutionary conserved “first line” host defense system. It integrates defense, regeneration, homeostasis and organ integrity. Central to innate immunity is the recognition of “pathogen associated molecular patterns” by macrophages and granulocytes, cell types of the immune system derived from HSCs.
Biomaterials placed in the human body also trigger responses by the innate immune system. They often induce adverse reactions such as acute and chronic inflammation, giant cell formation, fibrotic encapsulation and rejection, all hallmarks of the so-called FBR. The goal is to contribute to the rational design of biomaterials and achieve the desired, predictable responses.
Our approach to this end is the combined use of engineered animal as well as stem and immune cell-based models to identify mechanisms of biomaterial induced activation of the innate immune system.