Bone Marrow Microenvironment-On-Chip for Culture of Functional Hematopoietic Stem Cells

Abstract

Hematopoiesis takes place in the bone marrow and is supported by a complex cellular and molecular network in the bone marrow microenvironment. Commonly used models of the human bone marrow microenvironment include murine models and two-dimensional and three-dimensional tissue cultures. While these model systems have led to critical advances in the field, they fail to recapitulate many aspects of the human bone marrow. This has limited our understanding of human bone marrow pathophysiology and has led to deficiencies in therapy for many bone marrow pathologies such as bone marrow failure syndromes and leukemias. Therefore, we have developed a modular murine bone marrow microenvironment-on-chip using a commercially available microfluidic platform. This model includes a vascular channel separated from the bone marrow channel by a semi-porous membrane and incorporates critical components of the bone marrow microenvironment, including osteoblasts, endothelial cells, mesenchymal stem cells, and hematopoietic stem and progenitor cells. This system is capable of maintaining functional hematopoietic stem cells in vitro for at least 14 days at frequencies similar to what is found in the primary bone marrow. The modular nature of this system and its accessibility will allow for acceleration of our understanding of the bone marrow.

Immunity‐on‐a‐Chip: Integration of Immune Components into the Scheme of Organ‐on‐a‐Chip Systems

“…The hematopoietic function was maintained for 14 d. [248] Lymph node Compartmentalized miniaturized bioreactor with a porous membrane which enables B-cell activation and DC-T-cell crosstalk hence modeling human lymph node model (HuALN)…”

“…[204] Additionally, the device was tested with cells from patients with Shwachman-Diamond syndrome and reproduced key hematopoietic defects and led to the discovery of a neuabnormality. Another recent BM-on-chip by Sharipol et al [205] was fabricated using a commercially available microfluidic platform from Emulate Inc. (Emulate Chip S-1) (Figure 7b). This BM model includes a vascular channel separated from the bone marrow channel by a semiporous membrane, which contains osteoblasts, endothelial cells, mesenchymal stem cells, and hematopoietic stem and progenitor cells.…”

“…Reproduced under terms of the CC-BY license. [205] lymph travels from the collecting lymphatic vessels to the LNs, entering through afferent lymphatic vessels. The endothelial cells along the floor of the subcapsular sinus express cytokine receptors, such as CCL21 and CCR7.…”

Construction of Bone Hypoxic Microenvironment Based on Bone-on-a-Chip Platforms

“…Pluripotent hematopoietic stem cells and progenitor cells (HSPCs) are the source of all blood cell types. It is known that the bone marrow stem cell niche in which the HSPC are maintained is vital for their maintenance [ 106 , 107 ]. However, until now, no in vitro model has been presented that can truly simulate all aspects of the bone marrow niche and allow the long-term culture of HSPCs.…”

The Potential Role of 3D In Vitro Acute Myeloid Leukemia Culture Models in Understanding Drug Resistance in Leukemia Stem Cells

“…This model used mouse tissues that allowed for competitive repopulation experiments, the gold standard of HSC functional analysis. These studies highlighted the ability to maintain a highly functional HSC population for at least 2 weeks in vitro [ 23 ]. These results suggest that similar platforms are highly adaptable to in vitro studies of AML LSCs phenotype and function in future experiments.…”