A new model for the human bone marrow niche supports the culture of hematopoietic stem and progenitor cells

The bone marrow, a highly vascularized fibrous tissue, is the physiological niche of hematopoietic stem cells (HSCs) in the adult. There, HSCs can self-renew or differentiate into hematopoietic progenitor cells (HPCs) to produce daily all mature blood cells needed throughout life. The right balance between quiescence, self-renewal and differentiation is highly regulated by a close contact to cellular components (i.e. vascular endothelial cells, multipotent mesenchymal stromal cells) and non-cellular components (i.e. extracellular matrix, growth factors) of the bone marrow niche.

In vitro models of the hematopoietic system aim to support stemness and/or differentiation of hematopoietic stem and progenitor cells (HSPCs), by mimicking essential components of the bone marrow niche. Established in vitro HSPC niche models classically use immortalized stromal cell lines (feeder cells) or medium supplemented with growth factors. Such media have less supportive HSPC capacities over time than the feeder cells, proving the importance of cell-cell contact in such culture systems. However, the cell-cell interactions provided by the feeder cells in 2D co-cultures does not fully mimic the natural and complex 3D microenvironment of the bone marrow.

The aim of our study was to identify the potential of various primary cell types and hydrogels to support the culture of HSPCs in vitro in 3D, without the need of additional growth factors. Optimal HSPC support was obtained in presence of fat cells and bone cells, together with endothelial cells. When cultured in a bioactive hydrogel, the supportive cells self-assembled into a hypoxic stromal network that stimulated the production of mature blood cells, whilst maintaining the pool of immature HSPCs. HSPC clusters co-localized with the stromal network, in close proximity to sinusoidal endothelial cells.

Future perspectives
Our engineered primary 3D bone marrow model provides an easy and reliable model to further investigate the interactions between HSPCs and their surrounding niches (i.e. endosteal and perivascular niches). The 3D model is easy to manipulate by including or excluding cellular or non-cellular components or by interfering with specific cell-cell interactions. Overall, the 3D model will be useful to study the role of bone marrow niches in normal hematopoiesis as well as in the case of bone marrow related diseases.

Publication
A Human Hematopoietic Niche Model Supporting Hematopoietic Stem and Progenitor Cells In Vitro. Maaike V.J. Braham, Amélie S.P. Li Yim, Jara Garcia Mateos, Monique C. Minnema, Wouter J. A. Dhert, F. Cumhur Öner, Catherine Robin and Jacqueline Alblas. Advanced Healthcare Materials 2019, Apr 3:e1801444. DOI: 10.1002/adhm.201801444.