During early embryogenesis, the uterine environment undergoes marked biophysical changes that guide the embryonic cell fate. However, replicating these stage-specific cues in vitro remains challenging. Herein, we introduce a gelatin-based coacervate matrix with phase-transition-mediated tunable mechanics to recapitulate the biophysical cues of pre- and peri-implantation stages. Driven by reversible hydrophobic interactions, liquid-liquid phase separation produces coacervates with ultradynamic structures that enable dramatic volume expansion during cell proliferation in preimplantation stage. Furthermore, the liquid-like coacervate emulates the loosely organized immature extracellular matrix (ECM) of the uterine fluid environment, providing moderate cell-matrix interactions that preserve stemness. Additionally, the coacervate-solution transition allows the efficient harvesting of highly viable embryonic stem cell colonies. Moreover, upon stiffening through the coacervate-hydrogel transition, the matrix promotes peri-implantation-like invasive behaviors, including enhanced cell-matrix adhesion and secretion of ECM-degrading enzymes. These findings establish the biomimetic coacervate matrix as a versatile platform for clonal growth, stemness maintenance, and lineage initiation, offering new opportunities for developmental modeling and therapeutic applications.
Xie et al. (Tue,) studied this question.