Focus Areas

Regenerative therapies are gaining more and more attention as innovative therapeutic opportunities that could help treat diseases and disorders for which no satisfactory treatment options are currently available. Most therapeutic challenges exist in compromised patients due, for example, to old age, diabetes, immunodeficiency or complex infectious situations. It is essential to understand how endogenous healing is influenced in medically compromised conditions for the successful implementation of regenerative medicine approaches to relevant patient groups.

To this end we concentrate our research on the following four focus areas:

Cellular mechanisms in compromised healing

 

Cellular regenerative properties are dependent on the intrinsic function of the cell, but are also affected by the surrounding micro-environment, such as the extracellular matrix, paracrine mediators (e.g. growth factors or cytokines), pH, availability of nutrients, cell-cell interactions and other factors.

However, tissue engineering approaches focus mainly on the simple replacement of the damaged tissue without considering the surrounding environment. Taking into account that tissue damage is often associated with otherwise compromised conditions, such as heighten inflammation or impaired vascularization, it is not surprising that plain tissue replacement strategies often fail in clinical translation, as they underestimate the impact of the local milieu. Thus, we first need to obtain a better understanding of the influence of the local micro-environment on cellular functions in order to modulate and facilitate endogenous regenerative cascades by cellular therapies.

 

The objectives of this focus area are:

  • to establish patient specific cellular therapies by understanding how cellular properties change under compromised conditions, how these changes are influenced by intrinsic and extrinsic modulators and how this dampens regeneration in compromised patients;
  • to establish therapies to modulate the local milieu accordingly and thus to facilitate endogenous regenerative processes.

 

Steer cell-matrix interactions

 

The interactions of cells with their environments lies at the heart of all tissue formation processes. Interactions between the living cells and the surrounding matrix components control both the fate of progenitor cells (cell lineage) and the final properties (stiffness, size) of the formed tissue/organ. Cells ‘feel’ their environments and respond to it in various ways: by applying mechanical forces and shaping of the extracellular matrix (ECM); by secreting different ECM components and creating micro-geometries; or by transforming from one cell type to another. The ECM also affects the manner in which cells signal and communicate with each other, functioning either as a barrier or carrier for biochemical pathways and mechanical communication.

During recovery processes or pathological tissue formation, a new ECM is formed under sub-optimal organogenesis conditions (compromised blood flow, mechanical overload, need for large material quantities, compromised cell viability, restricted numbers of progenitor cells, sclerotic and scarred environments etc.). A huge therapeutic potential thus lies in taking control of the interactions between cells and their environments. Improving the healing response requires first a better understanding and then modulation of the interactions of cells with their immediate surroundings within the ECM.

 

The objectives of this focus area are:

  • to examine and understand how the morphology of both soft and hard tissues affects cell behavior and fate in health and disease and to understand the effects of normal and overload physical cues from the environment (pressure, confined geometries) on the mobility and architectural reshaping/response of cells;
  • to understand and modulate the ECM environment of cells in pathological conditions. The ultimate goal is to adjust the environment that the cells “feel”, thereby control the cell response and to counterbalance compromised healing situations.

Shape the inflammatory phase of regeneration

 

The immune system plays a key role in controlling the homeostasis of the body. For a long time, immunological research focused on the mechanisms of protection of infections and tumors as well as the immune-pathogenesis of diseases such as autoimmunity and allergy. However, recent data demonstrate that the innate immune system, including innate lymphoid cells (ILC) as well as the adaptive immune system, in particular T cells, are also major players in controlling tissue regeneration following trauma or chronic tissue remodeling. An imbalance between effector and regulatory pathways contributes to compromised regeneration by blocking stem cell recruitment and differentiation, reprogramming of the cellular and extracellular environment and altered perfusion etc.

Even if at the first view the mechanisms behind challenged homeostasis in compromised patients are different in distinct clinical situations, such as tumor growth, trauma, (auto/allo)-immune attack, there are many shared pathways modulated by modifiers like age and metabolic situation. For example, in undesired immune reactivity (autoimmunity, transplantation, post-traumatic regeneration), support of regulation by regulatory T cells might be of benefit, while in cancer patients we want to target undesired stroma-related immune regulation to improve anti-tumor defense.

Aging of the immune system, which is driven by chronic and/or repetitive antigen exposition, has a major impact on the intra-tissue balance of immune responsiveness. Biomarkers are available now that allow us to determine the individual “age” of the immune system and assist in risk stratification into “good and bad healer” (Reinke S. et al. Sci Transl Med 2013).

 

The focus area concentrates on two major issues

  • to specifically reshape the inflammatory response for supporting regeneration, we need a better understanding of the underlying mechanisms, which determine these responses and the development of biomarkers.
  • to reshape inflammatory (intra-tissue) reaction by targeted therapies, several tools will be developed and tested, such as cells, bioactive factors, biomaterials and combinations thereof.

 

Modeling, simulation and data analysis of regeneration processes

 

Today, digital research (modeling, simulation, data analysis and visualization) is an integral part of hypothesis driven approaches to gain an understanding of regenerative cascades and its modulators. However, most standard computational systems in medicine suffer from the fact that the transfer of information between different scales (molecular, cellular, tissue to organism) is still problematical. This focus area aims at integrating these different length scales within the research foci by interlinking the scientists in the Einstein Center with respect to the development and application of computational tools for scale-bridging understanding of regeneration processes. The objectives of the focus area are:

 

  • to mathematically model and simulate receptor binding and activation or inhibition processes at an atomic level aimed at uncovering their dependence on parameters of the cellular environment;
  • to build in silico models that allow testing and validation of biological hypotheses at the cellular and tissue level and to suggest further informative experiments.

 

 

 

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