Research Interests

Somatic cell therapy 

In recent years, there have been exciting advancements in the field of medicine, with the development of "advanced therapy medicinal products" (ATMPs). These groundbreaking therapies encompass gene therapy medicinal products, somatic cell therapy medicinal products, and biotechnologically processed tissue products. Throughout Europe, several ATMPs have been approved, and among them, somatic cell therapeutics hold great promise for treating a wide range of diseases in the future.

Now, these cell-based therapies have made their way into cardiovascular medicine, offering potential solutions for conditions such as cardiomyopathy, coronary infarction, and critical limb ischemia. However, it is essential to acknowledge that the predominantly used stem cell-based therapies have yielded only partially convincing results in some cases. Broad clinical application has been hindered by ethical concerns, the complexities of unexplained molecular mechanisms in tissue regeneration and angiogenesis (the formation of new blood vessels), and practical difficulties in cultivating embryonic and mesenchymal stem cells.

In response to these challenges, researchers are exploring targeted (de)differentiation and reprogramming of certain blood cells, specifically somatic blood mononuclear cells (e.g. monocytes). This approach could help us overcome many of the issues associated with using traditional stem cells in clinical settings.

As a result, scientists have identified "programmable cells of monocytic origin" (PCMO) and "regulatory macrophages" (Mreg) as promising alternatives to conventional stem cell-based therapies. Reprogrammed monocytes, such as PCMO and Mreg, have demonstrated potential applications in cell transplantation, preventing rejection reactions in transplant surgeries, and even in in vitro tissue engineering. Importantly, these cells exhibit characteristics of native monocytes, macrophages, and hematopoietic progenitor cells, making them versatile and functional in various therapeutic scenarios.

Notable features of PCMO and Mreg that could revolutionize cardiovascular medicine include their ability to secrete proteins that promote angiogenesis, their high cell plasticity, and the feasibility of both allogeneic (from a donor) and autologous (from the patient) transplantation. Moreover, their relatively simple isolation and production through in vitro cultivation streamline the process of obtaining these cells for therapeutic purposes.

To harness the full potential of PCMO and Mreg cells, we are engaged in exploring various experimental approaches. Our group is investigating the clinical use of these reprogrammed cells in treating diseases related to reduced oxygen and nutrient supply (ischemia), inflammation, and tissue remodeling processes. This includes studying the surface characteristics of these cells (CD surface expression) and analyzing the proteins they secrete (secretome) in controlled laboratory settings and living organisms, especially under normal and low-oxygen conditions (hypoxic).

The ongoing efforts also involve optimizing and modifying PCMO and Mreg cells to ensure their safe and effective application in clinical settings. By focusing on these innovative cell-based therapies, we aim to unlock new therapeutic possibilities that could provide hope and improved outcomes for patients suffering from cardiovascular diseases. 

Important publications of the research group on somatic cell therapy

1. Albrecht M, Hummitzsch L, Rusch R, Eimer C, Rusch M, Hess K, Steinfath M, Cremer J, Fändrich F, Berndt R, Zitta K Large extracellular vesicles derived from human regulatory macrophages (L-EVMreg) attenuate CD3/CD28-induced T-cell activation in vitro. J Mol Med, 2023. https://doi.org/10.1007/s00109-023-02374-9.

2. Albrecht M, Hummitzsch L, Rusch R, Hess K, Steinfath M, Cremer J, Lichte F, Fändrich F, Berndt R, Zitta K Characterization of large extracellular vesicles (L-EV) derived from human regulatory macrophages (Mreg): novel mediators in wound healing and angiogenesis? J Transl Med, 2023. 21, 61. 

3. Berndt R, Albrecht M and Rusch R Strategies to overcome the barrier of ischemic microenvironment in cell therapy of cardiovascular disease. Int J Mol Sci, 2021. 22(5):2312. 

4. Hummitzsch L, Berndt R, Kott M, Rusch R, Faendrich F, Gruenewald M, Steinfath M, Albrecht M, Zitta K Hypoxia directed migration of human naïve monocytes is associated with an attenuation of cytokine release: indications for a key role of CCL26. J Transl Med, 2020. 18, 404. 

5. Hummitzsch L, Albrecht M, Zitta K, Hess K, Parczany K, Rusch R, Cremer J, Steinfath M, Haneya A, Faendrich F, Rouven B Human monocytes subjected to ischemia/reperfusion injury inhibit angiogenesis and wound healing in vitro. Cell Prolif, 2020. 00:e12753. 

6. Hummitzsch L, Zitta K, Rusch R, Cremer J, Steinfath M, Faendrich F, Berndt R, Albrecht M Characterization of the angiogenic potential of human regulatory macrophages (Mreg) after ischemia/reperfusion injury in vitro. Stem Cells Int, 2019. article ID 3725863.

7. Berndt R, Hummitzsch L, Hess K, Albrecht M, Zitta K, Rusch R, Sarras B, Bayer A, Cremer J, Faendrich F, Gross J Allogenic transplantation of programmable cells of monocytic origin (PCMO) improves angiogenesis and tissue recovery in critical limb ischemia (CLI): a translational approach. Stem Cell Res Ther, 2018; 9:17. 

Ischemic conditioning 

 Our bodies possess remarkable adaptive mechanisms to cope with challenging situations, and one such mechanism is ischemic conditioning. This process occurs at the molecular and cellular levels and allows our organs to develop a certain resistance to ischemia, a condition where blood flow to a tissue is decreased or absent. This natural defense mechanism can be triggered in two ways: either by brief, non-injurious episodes of ischemia directly at the affected organ (ischemic conditioning) or from a distance at other organs (remote ischemic conditioning).

There are three types of ischemic conditioning based on the timing of the protective stimulus: pre-conditioning (before the harmful event), per-conditioning (during the event), and post-conditioning (after the event).

The concept of ischemic preconditioning was first introduced in 1986 when researchers discovered that brief, nonlethal periods of cardiac ischemia and reperfusion could significantly reduce the size of a subsequent heart attack. Moreover, this protective effect was not limited to the heart; remote ischemic conditioning showed that interrupting blood flow to one specific coronary artery reduced the size of a myocardial infarction occurring in another part of the heart. This idea was further developed, and studies found that even a simple intervention like temporarily interrupting blood flow in the upper arm through a blood pressure cuff could protect the heart from damage caused by ischemia and reperfusion.

This protective mechanism is not exclusive to the heart but extends to other organs as well, including the brain, liver, kidney, lung, and intestine. However, it is important to note that certain pre-existing conditions and medications can weaken the protective effect of ischemic conditioning. Conditions such as diabetes, high blood pressure, high cholesterol, and the use of specific drugs like antidiabetics, ACE inhibitors, AT-1 blockers, and anesthetics like propofol have been shown to attenuate the organ-protective effects.

The mechanisms behind ischemic conditioning are complex and involve a variety of signaling pathways. Understanding these intricate mechanisms is crucial for optimizing and applying ischemic conditioning in clinical settings. Our group has been diligently studying these mechanisms using various methods, including cell culture models, animal experiments, and patient studies. 

In conclusion, ischemic conditioning is a fascinating natural defense mechanism that provides protection against the damage caused by reduced blood flow to our organs. Harnessing the power of this process could lead to innovative and cost-effective therapies with minimal side effects. 

Important publications of the research group on the topic of ischemic conditioning

1. Hummitzsch L, Zitta K, Fritze L, Monnens J, Vollertsen P, Lindner M, Rusch R, Hess K, Gruenewald M, Steinfath M, Fändrich F, Berndt R, Albrecht M Effects of remote ischemic preconditioning (RIPC) and chronic remote ischemic preconditioning (cRIPC) on levels of plasma cytokines, cell surface characteristics of monocytes and in vitro angiogenesis: a pilot study. Basic Res Cardiol, 2021. 116, 60. 

2. Wong YL, Lautenschläger I, Hummitzsch L, Zitta K, Cossais F, Wedel T, Rusch R, Berndt R, Gruenewald M, Weiler N, Steinfath M, Albrecht M Effects of different ischemic preconditioning strategies on physiological and cellular mechanisms of intestinal ischemia/reperfusion injury: implication from an isolated perfused rat small intestine model. Plos One, 2021. 16(9):e0256957. 

3. Hummitzsch L, Zitta K, Berndt R, Wong Y, Rusch R, Hess K, Wedel T, Gruenewald M, Cremer J, Steinfath M, Albrecht M Remote ischemic preconditioning attenuates intestinal mucosal damage: insight from a rat model of ischemia-reperfusion injury. J Transl Med, 2019. 29;17(1):136. 

4. Meybohm P et al. The RIPHeart-Study Investigator Group (Albrecht M et al.) Remote Ischemic Preconditioning for Heart Surgery (RIPHeart-Study): A multicenter randomized controlled trial. N Engl J Med, 2015; 373:1397-407. 

5. Albrecht M, Zitta K, Bein B, Wennemuth G, Broch O, Renner J, Schuett T, Lauer F, Maahs D, Hummitzsch L, Cremer J, Zacharowski K, Meybohm P Remote ischemic preconditioning regulates HIF-1α levels, apoptosis and inflammation in heart tissue of cardiosurgical patients. Basic Res Cardiol, 2013; 108:314-326. 

3D printing: cardiovascular bioengineering

Developing artificial bypass grafts remains a significant challenge in the world of cardiovascular medicine. These grafts are essential in cardiac and vascular surgeries, where they serve as vital conduits to restore blood flow to blocked or damaged blood vessels. Currently, surgeons use arterial or venous grafts in cardiac procedures, while a range of artificial bypass grafts made from various materials, such as polymers or xenografts, are employed in vascular surgeries. However, the shortage of suitable "graft material" and the limited success rates of some artificial grafts pose obstacles in these critical medical interventions.

To address these challenges, researchers have been working on generating bypass grafts from biological materials. Early attempts in the late 1970s involved using modified umbilical cord veins as peripheral extremity bypasses, but these had limitations. In subsequent years, xenografts were developed, consisting of a mechanical scaffold combined with endothelial cells to mimic natural blood vessels. More recently, innovative experimental techniques emerged from the field of bioengineering, focusing on repopulating a decellularized biomatrix with auto- or allogeneic cells in a specialized bioreactor. While some of these experimental studies show promise, only a few have reached the stage of potential clinical application.

Considering the challenges posed by the limited availability of suitable bypass grafts in cardiovascular surgery and the suboptimal performance of artificial grafts in peripheral vascular surgery, our group is dedicated to a groundbreaking approach: 3D bioprinting using an alginate/peptide-based bioink combined with vital cells. This cutting-edge technology allows us to create a biological artificial graft that can be used for both auto- and allogeneic implantation. By carefully designing the structural and theoretical aspects of this innovative graft, we aim to pave the way for its eventual translation into clinical applications. 

With the potential to revolutionize cardiovascular medicine, our pursuit of biological artificial bypass grafts holds great promise. This advancement could significantly improve patient outcomes in cardiac and peripheral vascular surgeries, offering a more readily available and effective solution to restore blood flow and save lives. 

Important publications of the research group on the topic of 3D printing and cardiovascular bioengineering

1. Pfarr J, Zitta K, Hummitzsch L, Lutter G, Steinfath M, Jansen O, Tiwari S, Haj Mohamad F, Knueppel P, Lichte F, Mehdorn AS, Kraas J, Hess K, Faendrich F, Cremer J, Rusch R, Grocholl J, Albrecht M, Berndt R 4D printing of bioartificial, small-diameter vascular grafts with human-scale characteristics and functional integrity. Adv. Mater. Technol. 2024, 2301785. https://doi.org/10.1002/admt.202301785. 

2. Rusch R, Trentmann J, Hummitzsch L, Rusch M, Aludin S, Haneya A, Albrecht M, Puehler T, Cremer J, Berndt R Effectiveness and safety of percutaneous thrombectomy devices: Comparison of Rotarex® and Angiojet® in a physiological circulation model. Eur J Vasc Endovasc Surg, 2020. 13;S1078-5884(20)30062-9. 

3. Rusch R, Trentmann J, Hummitzsch L, Rusch M, Aludin S, Haneya A, Albrecht M, Schäfer JP, Puehler T, Cremer J, Berndt R Feasibility of a circulation model for the assessment of endovascular thrombectomy and perioperative thromboembolism in vitro. Sci Rep, 2019. 9(1):17356. 

Pfarr et al., Adv. Mater. Technol. 2024