PEG-PCL Copolymers Reinstating Human Mesenchymal Stem Cell Potency: Study of Structure-Function Relationship

Abstract

Regenerative medicine has the potential to revolutionize how medical professionals approach combating and treating disease. Over the past several decades, human mesenchymal stem cells (hMSCs) have become one of the most promising cell sources for regenerative medicine due to their autologous availability, self-renewal capacity, angiogenic effect, immunomodulatory effects, and multi-lineage differentiation potential. However, the individuals who would gain the most from stem cell-based therapies are typically those of advanced age, and the hMSCs they would otherwise provide are accompanied by detrimental abnormalities such as reduced self-renewal and differentiation potentials, thereby limiting their therapeutic efficacy. Furthermore, hMSC-mediated tissue regeneration would require exhaustive in vitro expansion to achieve sufficient numbers, and serially-expanded hMSCs demonstrate passage-associated abnormalities. This dissertation project aimed at tackling a significant issue in clinical translation of hMSCs, namely looking for material compositions that promote hMSC stem cell health for ex vivo expansion. A library of combinatorial copolymers utilizing FDA-approved synthetic polymers poly(ε-caprolactone) (PCL) and poly(ethylene glycol) (PEG) was synthesized and then fabricated into thin spin-coated films for cell culture. hMSC phenotype was characterized across the copolymer library and the copolymer surface features were interrogated by x-ray scattering and super resolution imaging methods. An ideal candidate copolymer was identified followed by verifying a molecular mechanism for the pro-therapeutic hMSC phenotype and demonstrating the universal effect of the copolymer by culturing patient-derived hMSC instead of commercial hMSCs. These findings will contribute to future biomaterial design to enable effective translation and scalability of regenerative medicine strategies using autologous hMSCs.