Researchers build bone marrow model entirely from human cells

Good news!

"Scientists have successfully engineered the first entirely human-made bone marrow system in a lab, a key development for advanced blood research."

"... Now, researchers have succeeded for the first time in recreating this cellular complexity in the laboratory using only human cells. The novel system could reduce the need for animal experiments for many applications ...

Typically, bone marrow research relies heavily on animal models and oversimplified cell cultures in the laboratory. Now, researchers from the Department of Biomedicine at the University of Basel and University Hospital Basel have developed a realistic model of the bone marrow engineered entirely from human cells. ..."

From the highlights and abstract:

"Highlights

• 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

Summary

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."

Researchers build bone marrow model entirely from human cells | University of Basel

Macro-scale, scaffold-assisted model of the human bone marrow endosteal niche using hiPSC-vascularized osteoblastic organoids (open access)

Credits: The Flyover

Graphical abstract

Scientists uncover glioblastoma's impact on skull and immune system

Good news! Cancer is history (soon)! However, treating glioblastoma may even be more complicated than before.

"... Further investigation of human brain scans found that skull thickness had been altered by the tumors, particularly where bones fuse. ...

The researchers found that, in the mice, the erosion of the skull increased the number and size of skull-to-bone channels present, which they believed could be allowing tumor cells to impact marrow, affecting the body's immune system. Through single-cell RNA sequencing, the team indeed saw that glioblastoma upended the skull bone marrow's environment – filling it with pro-inflammatory neutrophils while decimating cancer-fighting antibody-producing B cells.

“The skull-to-brain channels allow an influx of these numerous pro-inflammatory cells from the skull marrow to the tumor, rendering the glioblastoma increasingly aggressive and, all too often, untreatable,” ..."

"Scientists ... have shown for the first time that glioblastoma—the deadliest form of brain cancer—affects not just the brain but also erodes the skull, alters the makeup of skull marrow, and interferes with the body’s immune response. Drugs intended to inhibit skull-bone loss made the cancer more aggressive ...

To find out, they gave mice with glioblastoma tumors two different drugs approved by the U.S. Food and Drug Administration for treating osteoporosis. Both drugs (zoledronic acid and denosumab) halted skull erosion—but one of them (zoledronic acid) also fueled tumor progression in one type of glioblastoma. ..."

From the abstract:

"The skull marrow niche has recently been identified as a reservoir that supplies the brain with monocytes and neutrophils in the context of disease and injury, but its role in brain cancers remains unknown.

Here we show that glioblastoma, the most malignant type of brain tumor, induces calvarial bone abnormalities in murine models and patients with glioblastoma, altering osteoclast activities and increasing the number of skull channels in mice.

Single-cell RNA sequencing revealed glioblastoma-mediated alterations in the immune landscape of skull marrow and femoral bone marrow, including expansion of neutrophils and deterioration of various B cell subsets.

In vivo inhibition of bone resorption reduced bone abnormalities, but promoted tumor progression in mesenchymal subtype tumors.

This also abolished the survival benefit of the checkpoint inhibitor anti-PD-L1, by reducing activated T cell and increasing inflammatory neutrophil numbers. Together, these data provide insight into how brain tumors affect skull bone and the immune environment."

Scientists uncover glioblastoma's impact on skull "For the first time, scientists have detailed how a deadly brain cancer has a unique path of progression, aggressively eating away at the skull itself – and how drugs to impede this end up making it worse."

Glioblastomas Affect Much More Than Just the Brain (original news release) "Finding Links Between Tumors and Skull Bone Marrow Could Lead to New Treatment Strategies"

Brain tumors induce widespread disruption of calvarial bone and alteration of skull marrow immune landscape (open access)

Fig. 1: GBM induces calvarial bone abnormality and OC activity in several anatomical regions of the calvarium delineating osteogenic edges adjacent to the skull sutures.

Bone marrow-on-a-chip models damage and disease

Recently, I blogged here about body-on-a-chip!  Now, a new organ-on-a chip has been reported! Amazing stuff!

"Until David Chou, Viktoras Frismantas and their colleagues developed the bone marrow chip, the only way to study living marrow tissue effectively was to take painful biopsies from the bones. ... we are in a position to assist in the design of human clinical trials for rare genetic disorders and advance personalized medicine in ways not possible before"

Bone marrow-on-a-chip models damage and disease – Physics World: Human bone marrow chip provides a reliable model to study bone marrow damage by radiation, drugs and disease