Developing a 3D bioprinted bone marrow model to probe hematopoietic stem cell mobilization in response to age-related changes in stiffness gradients

About This Grant

PROJECT SUMMARY/ABSTRACT Hematopoietic stem cell (HSC) mobilization from the bone marrow to the peripheral blood is essential for bone marrow transplants, a life-saving treatment for hematological malignancies such as leukemia, lymphoma, and multiple myeloma. Poor mobilization remains a major clinical challenge, particularly in older patients (>60 years old), who represent the majority of those diagnosed with blood cancers yet often exhibit diminished responses to mobilization treatments. Age-related changes to the bone marrow microenvironment, specifically changes in microenvironmental stiffness, are believed to contribute to these mobilization failures. It has been recently measured that the bone marrow contains unique stiffness values in each identified sub-niche and observations in age-related stiffening has been reported; however, challenges with accurately measuring these values in vivo limits our understanding on how these gradients change with age. Existing 3D bone marrow models fail to capture the nonlinear stiffness gradients observed in vivo; therefore, the long-term objective of this proposal is to improve clinical predictions of a patient’s ability to successfully mobilize HSCs for a transplant. To achieve this objective, we will engineer a heterogenous, multi-niched bone marrow model with methacryloyl gelatin (GelMA) bioinks and extrusion bioprinting technologies to decouple the effects of young and aged stiffness environments on HSC mobilization. We expect the precision and automation of this approach will more accurately recapitulate the spatially transient stiffness environments of the native sub-niches. This research will target two major knowledge gaps: 1) how nonlinear gradients and age-related changes in microenvironmental stiffness influence HSC migration and phenotype, and 2) how to improve the ability to predict a patient’s ability to mobilize HSCs for more effective and personalized transplant strategies. The overarching hypothesis of this project is that age-related stiffening is a key microenvironmental cue which restricts HSC mobilization to the peripheral blood; and the mobilization of HSCs encapsulated in in vitro biofabricated models with physiomimetic stiffnesses of young and aged bone marrow sub-niches can predict the mobilization of in vivo HSCs to the peripheral blood. I will test this hypothesis through two specific aims; 1) assess the mobilization behavior of HSCs in response to GelMA stiffness gradients, and 2) correlate in vivo mobilization behavior in young and aged mice with in vitro behavior using bioprinted bone marrow models. We expect to identify the role of transient nonlinear stiffness gradients and age-related stiffness changes on HSC mobilization behavior. Furthermore, this work will improve strategies for predicting patient-specific mobilization outcomes for patients with hematological malignancies.