Immunomodulatory effects of mesenchymal stem/stromal cell efferocytosis by monocytes
Creators: name: Schrodt, Michael Verle
Publisher: name: University of Iowa
Year: 2023
Subjects: Efferocytosis
Imunosuppression
Monocyte
MSC
public abstract
Immunotherapy

description: The immunosuppressive capability of mesenchymal stem/stromal cells (MSCs) demonstrated over the past two decades has fueled an eagerness to develop therapies using MSCs to treat a myriad of immune-mediated diseases. MSCs can alleviate inflammation and promote immune tolerance in several disease models, largely through an array of trophic factor signaling pathways. However, due to the diversity of MSC mechanisms of action and differences in diseases treated with MSCs, developing effective MSC therapies for clinical use has been slow and challenging. While MSC therapies have exhibited promising data in clinical trials, clinical approval for a MSC therapy remains elusive. The diverse nature of MSC mechanism of action is further muddied by paradoxical observations: MSCs exhibit limited persistence in vivo, yet they promote durable and robust immunomodulatory responses. A novel mechanism of action has emerged based on observations that host monocytes and macrophages are associated with the clearance of MSCs: efferocytosis. Efferocytosis is a natural mechanism the body employs to clear dead and dying cells while minimizing inflammatory responses. Evidence has accumulated to support this hypothesis, but isolating the effects of MSC-mediated efferocytosis from trophic factor signaling has not been fully studied. To realize the full potential of MSC therapies, it is critical to understand the various ways MSCs can exert their immunomodulatory capabilities, including via efferocytosis.
description: The aim of this thesis is to evaluate how MSC viability affects monocyte immunomodulatory efficacy through efferocytosis. To accomplish this, it is important to understand why MSCs are actively being explored as immunomodulatory therapeutics for treating immune diseases and how efferocytosis has emerged as a potential mechanism of action in this regard. In Chapter 1, I provide detailed background information of MSC immunomodulatory capability and mechanisms of action that culminates with the current gaps in knowledge regarding the effects of MSC efferocytosis on the human immune system.
description: The study of MSC efferocytosis explored in this thesis required extensive use of flow cytometry, specifically spectral flow cytometry, and, therefore, Chapter 2 is provides a thorough discussion of how flow cytometry works as well as the methods incorporated for biological inquiry. The purpose of the chapter is to be a comprehensive yet approachable reference for anyone who could benefit from flow cytometry in their research. Chapter 3 highlights how MSC viability affects monocyte phenotype and function via efferocytosis and, ultimately, the impact that efferocytosis of MSC material can have on immune-mediated diseases.
description: The results presented within this dissertation demonstrate the importance of MSC viability in promoting immunosuppression via monocyte efferocytosis in different disease contexts. Therefore, MSC efferocytosis should be considered as a potential mechanism of action that could have a significant impact when developing MSC therapies for different disease indications. Additionally, the viability status of the MSC product should be considered for potency testing of MSC therapies to ensure the best product is utilized for a given indication. Lastly, this research demonstrates the need to explore the efficacy of MSC therapies in conditions with significant monocyte depletion or adverse monocyte health. Evaluating the monocyte health of potential candidates for MSC therapies could identify individuals who may not benefit from a specific product.