The fetal liver microenvironment as a developmental framework for hematopoietic stem cell expansion

Hematopoietic stem cells (HSCs) sustain lifelong blood production through self-renewal and multilineage differentiation. Transplantation can be curative for selected hematologic malignancies and nonmalignant disorders, but donor availability, HLA matching, graft cell dose, and durable engraftment remain important constraints. Ex vivo expansion and pluripotent stem cell-derived hematopoiesis could broaden access, provided that expanded cells retain long-term repopulating function. In vitro-generated hematopoietic cells often show limited yield, incomplete maturation, and variable engraftment. Cytokine cocktails, stromal feeders, small molecules, and biomimetic niches can increase phenotypically defined HSC/HSPC numbers, but numerical expansion does not necessarily indicate expansion of bona fide long-term repopulating HSCs. During development, the fetal liver (FL) supports stage-dependent HSC expansion, maturation, and progenitor differentiation. Some FL-derived populations show greater repopulating activity than adult bone marrow- or cord blood-derived populations in specific preclinical assays, although results vary with developmental stage, phenotype, dose, and transplantation model. Organoid and bioengineering technologies may provide experimental systems for reconstructing selected FL niche features, but current fetal liver organoids (FLOs) have not been shown consistently to generate or expand transplantable long-term HSCs. This narrative review synthesizes evidence on the cellular, molecular, signaling, and biophysical features of the FL niche and considers how selected features could inform FL-inspired organoid and culture models. We propose these models primarily as experimental platforms for defining the niche requirements underlying HSC identity, maturation, and long-term repopulating activity, and for testing strategies to improve the generation, maintenance, or expansion of functional HSCs. Their translational potential remains to be established through a clear distinction between HSC and progenitor expansion and rigorous validation using standardized long-term functional assays.