Three-Dimensional Human Bone Marrow Organoids for the Study and Application of Normal and Abnormal Hematoimmunopoiesis

Abstract

Hematoimmunopoiesis takes place in the adult human bone marrow (BM), which is composed of heterogeneous niches with complex architecture that enables tight regulation of homeostatic and stress responses. There is a paucity of representative culture systems that recapitulate the heterogeneous three-dimensional (3D) human BM microenvironment and that can endogenously produce soluble factors and extracellular matrix that deliver culture fidelity for the study of both normal and abnormal hematopoiesis. Native BM lymphoid populations are also poorly represented in current in vitro and in vivo models, creating challenges for the study and treatment of BM immunopathology. BM organoid models leverage normal 3D organ structure to recreate functional niche microenvironments. Our focus herein is to review the current state of the art in the use of 3D BM organoids, focusing on their capacities to recreate critical quality attributes of the in vivo BM microenvironment for the study of human normal and abnormal hematopoiesis.

Figure 1. Human BM structure and organization.

A) Adult human BM is located within cancellous tissue of mainly the long bones (shown here), pelvis, sternum, ribs, vertebrae and skull, and has a rich arterial supply. B) Paratrabecular regions are lined with osteoblasts and other supportive stromal cells, and constitute the endosteal compartment supporting one of the HSPC niches. The perivascular niche abuts the sinusoid towards which multilineal differentiated cells progress as they mature for release into the peripheral blood circulation. Extracellular matrix permits cell, cytokine and other soluble factor retention, and niche attachment as well as maintenance of the complex architecture and heterogenous cellular maturation during homeostasis and stress states. Erythroblastic islands are key components of the BM and highlight the dependence of normal hematopoiesis on the function of innate immune cells, finely tunable to the cytokine and stress response.

Figure 2. 3D BM models for the culture of human HSPCs or leukemia cells.

Stromal feeder cells are often added to create a supportive microenvironment. A) 3D Static models and B) Perfused models utilize a porous scaffold or hydrogel. C) Murine/Scaffold hybrid models use a murine host to implant a scaffold seeded with human cells, generating a humanized microenvironment with recruitment of murine cellular and humoral factors, including vascularization. D) Microfluidic devices recreate select BM environments on-a-chip. Each discrete and interconnected chamber recreates a particular BM compartment wherein few cells form niches to mimic BM interactions, e.g. adhesion, while receiving shear stress.