Macro-scale, scaffold-assisted model of the human bone marrow endosteal niche using hiPSC-vascularized osteoblastic organoids
Qing Li, Marina Nikolova, Gangyu Zhang, Igor Červenka, Federica Valigi, Dominik Bürri, Evelia Plantier, Andrea Mazzoleni, Anaïs Lamouline, Juerg Schwaller, Barbara Treutlein, Iván Martín, Andrés García‐García
Abstract
Endosteal bone marrow (BM) niches are crucial to sustain non-steady-state hematopoiesis but are challenging to be modeled in their cellular and molecular complexity in standardized, human settings. We report a developmentally guided approach to generate a macro-scale organotypic model of BM endosteal niches (engineered vascularized osteoblastic niche [eVON]) based on human induced pluripotent stem cells and porous hydroxyapatite scaffolds. The eVON contains long-lasting vascular networks covered by pericytes and neural fibers within an osteogenic matrix. Key niche signals ( CXCL12 , KITLG , and vascular endothelial growth factor A [ VEGFA ]) are expressed in human-specific patterns. The system supports hematopoiesis in vitro and preserves hematopoietic stem and progenitor cell (HSPC) multilineage repopulation capacity in vivo . eVON perturbations at cellular (removing vasculature) and molecular (deregulating VEGF-A and CXCL12 signaling) levels enabled the investigation of the contribution of endosteal vasculature to myelopoiesis. The eVON faithfully captures phenotypic, structural, and functional features of human endosteal BM, enabling the study of pathophysiological interactions with hematopoietic cells. • eVON model recapitulates molecular and cellular features of native BM endosteal niches • Endosteal vasculature enhances human myelopoiesis in the eVON • eVON preserves HSPC multilineage repopulating capacity • VEGF-A, CXCL12, and SCF signaling are active and could be perturbed in the eVON Li et al. present a 3D in vitro bone marrow model that faithfully captures phenotypic, structural, and functional features of human endosteal bone marrow niches, enabling the study of pathophysiological interactions between hematopoietic stem and progenitor cells and their microenvironment in fully human settings.