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The design of reliable biocompatible and biodegradable scaffolds remains one of the most important challenges for tissue engineering. In fact, properly designed scaffolds must display an adequate and interconnected porosity to facilitate cell spreading and colonization of the inner layers, and must release physical signals concurring to modulate cell function to ultimately drive cell fate. In this study, a combination of optimal mechanical and biochemical properties has been considered to design a one-component three-dimensional (3D) multitextured hydrogel scaffold to favor cell-scaffold interactions. A polyethylene glycol diacrylate woodpile (PEGDa-Wp) structure of the order of 100 μm has been manufactured using a microstereolithography process. Subsequently, the PEGDa-Wp has been embedded in a PEGDa hydrogel to obtain a 3D scaffold-in-scaffold (3D-SS) system. Finally, the 3D-SS capability to address cell fate has been assessed using human Lin− Sca-1+ cardiac progenitor cells (hCPCs). Results have shown that a multitextured 3D scaffold represents a favorable microenvironment to promote hCPC differentiation and orientation. In fact, while cultured on 3D-SS, hCPCs adopt an ordered 3D spatial orientation and activate the expression of structural proteins, such as the α-sarcomeric actinin, a specific marker of the cardiomyocyte phenotype, and connexin 43, the principal gap junction protein of the heart. Although preliminary, this study demonstrates that complex multitextured scaffolds closely mimicking the extracellular matrix structure and function are efficient in driving progenitor cell fate. A leap forward will be determined by the use of advanced 3D printing technologies that will improve multitextured scaffold manufacturing and their biological efficiency. [ABSTRACT FROM AUTHOR]