Biomaterials directed activation of a cryostable therapeutic secretome in induced pluripotent stem cell derived mesenchymal stromal cells

Abstract

Mesenchymal stem cell therapy has suffered from wide variability in clinical efficacy, largely due to heterogeneous starting cell populations and large-scale cell death during and after implantation. Optimizing the manufacturing process has led to reproducible cell populations that can be cryopreserved for clinical applications.Nevertheless, ensuring a reproducible cell state that persists after cryopreservation remains a significant challenge, and is necessary to ensure reproducible clinical outcomes. Here we demonstrate how matrix-conjugated hydrogel cell culture materials can normalize a population of induced pluripotent stem cell derived mesenchymal stem cells (iPSC-MSCs) to display a defined secretory profile that promotes enhanced neovascularization in vitro and in vivo. Using a protein-conjugated biomaterials screen we identified two conditions-1 kPa collagen and 10 kPa fibronectin coated polyacrylamide gels-that promote reproducible secretion of pro-angiogenic and immunomodulatory cytokines from iPSC-MSCs that enhance tubulogenesis of endothelial cells in Geltrex and neovascularization in chick chorioallantoic membranes. Using defined culture substrates alone, we demonstrate maintenance of secretory activity after cryopreservation for the first time. This advance provides a simple and scalable approach for cell engineering and subsequent manufacturing, toward normalizing and priming a desired cell activity for clinical regenerative medicine.

Mesenchymal stem cell‐secretome laden photopolymerizable hydrogels for wound healing

“…The MSC derived secretome has gained considerable interest for wound healing applications due to its anti-inflammatory, immunomodulatory, and angiogenic potential. 35,36 Because of their short half-life, rapid clearance into the blood stream, accumulation in the vital organs, and high cost of production necessitate the development of a sustained delivery platform of MSC-secretome. To address this, the encapsulation of secretome in biocompatible and biodegradable soft hydrogels for controlled release has emerged as a promising approach.…”

Bioregenerative Applications of the Human Mesenchymal Stem Cell- Derived Secretome: Part-I

“…While these therapies should still test the pluripotency and genomic stability of their MSCs, the risk of unwanted differentiation or malignant cell transfection is nullified with cell-free treatments [64,159,160]. Cell-free products could be produced in dynamically controlled laboratory conditions, increasing production rates and maximizing MSC secretion efficiency.…”