ISS: Biomanufacturing of Mesenchymal Stem Cell Secretomes for Tissue Regeneration

About This Grant

Mesenchymal stem cells (MSC) are a special type of cell that can reduce inflammation and help rebuild bone, cartilage, and other muscle and skeletal tissues. MSC can be grown and multiplied outside of the body for use as therapies, but the MSC lose their restorative abilities after being cultured for a long time or in tissues due to disease and aging. One possible cause for this decline is that MSC function is altered by physical forces, including interaction with growth supports and gravity. It is not well understood how physical forces change MSC pro- or anti-inflammatory strength. The goal of this project is to investigate how mechanical forces from growth substrate rigidity and microgravity cause MSC to stimulate or suppress the body's immune response, which is important information for MSC therapeutic effectiveness and manufacturing. MSC grown on tiny collagen-coated beads of defined rigidity will be cultured at the International Space Station (ISS) and on Earth. Changes in MSC function and inflammatory responses will be characterized upon return to Earth. This work will seek to identify which signals are altered by physical cues and potential medications that support cell function in MSC. These results look to inform the design of culture systems to model disease and make high-quality MSC. This project will foster workforce development by training students across multiple levels in biomaterial engineering and cell biology, strengthening the pipeline of future scientists and engineers in cell biomanufacturing and space research. While engineered substrates have advanced our understanding of MSC mechanobiology, gravitational constraints limit our ability to fully explore mechanical unloading, a key factor that may affect regenerative properties and reveal mechanosignals masked by gravity. This project leverages a microcarrier platform and microgravity to investigate how mechanical forces influence the function and immunomodulatory fate of MSC. Specifically, this study will examine how matrix rigidity alters the interferon-γ (IFN-γ)–driven immunomodulatory response of human MSCs in real microgravity, simulated microgravity, and normal gravity environments. The central hypothesis is that altered load, sensed through the collagen–integrin axis and the mechanoresponsive co-transcription factors YAP and TAZ, reprograms downstream signaling and leads to shifts in cell function and potency. MSC will be expanded on engineered microcarriers whose cores have precisely tuned stiffness and whose surfaces present integrin-binding ligands, creating a defined mechanical niche. Objective 1 looks to quantify how matrix stiffness and gravity level shape IFN-γ–driven signaling and will map the transcriptomic reprogramming across the broad spectrum of mechanotransduction pathways. Objective 2 seeks to determine how these mechanical inputs influence regenerative outputs with an emphasis on the secretome and will evaluate targeted interventions to preserve or enhance therapeutic efficacy. By tracking both cytokines and microRNA-enriched extracellular vesicles, the immediate immunomodulatory responses and the longer-term regulatory programs that shape MSC fate and tissue function will be captured. The resulting mechanistic insights will guide the rational design of culture platforms and biomanufacturing strategies for disease modeling and cell-based therapies on Earth. In parallel, the project will advance the cell-manufacturing workforce while delivering foundational insights into MSC behavior. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.