Bone marrow and stem cell insights to improve cancer treatment

05 September 2013

The intact bone marrow microenvironment using a combination of different types of microscopy and labelling with fluorescent dyes.

Image: The intact bone marrow microenvironment using a combination of different types of microscopy and labelling with fluorescent dyes.

New research has overturned widely accepted ideas about certain characteristics of haematopoietic stem cells (HSCs), which are found in the bone marrow and generate all the blood cells in a person's body. 

The work, from Cancer Research UK's London Research Institute (LRI; now part of the Francis Crick Institute), provides important insights into the structure and function of bone marrow and what happens in leukaemia and when cancer spreads to the bone. It is hoped to lead to improved testing of drugs as well as the design of more targeted and less toxic cancer treatments.

For their study, Dominique Bonnet's team at LRI used chemical probes labelled with a fluorescent dye to visualise HSCs at the whole body and microscopic levels within live animals or tissues. They also used a gene called luciferase from the firefly to make the stem cells glow, which allowed them to be tracked with very high sensitivity at the whole body level.

Dr Bonnet explained: "The permanent production of all blood cells relies on the capacity of HSCs to self-renew and generate mature blood cells. HSCs reside in the bone marrow where they are tightly regulated by a specialised microenvironment - this is called a stem cell niche.

"The ends of the long bones - trabecular regions - are believed to be enriched in stem cell niches. Within stem cell niches, vascular niches (around blood vessels, which are highly oxygenated) and osteoblastic niches (at the bone surface, which lacks oxygen) are two distinct structures that are thought to be far apart from each other. This distance explains how a decreasing gradient of oxygen and the low oxygen status of the osteoblastic niche occurs."

The scientists found that the bone marrow - including the bone surface where osteoblastic niches are - is very well supplied with blood vessels and blood. Despite this, they confirmed that most HSCs display clear evidence of low oxygen.

The team also discovered that in fact HSCs are not preferentially located in the trabecular bone as previously thought, but are evenly distributed across the skeleton.

However, when they carried out bone marrow transplants by infusion of HSCs into a vein, the researchers found preferential seeding and reconstitution of the trabecular bone regions. "We showed that the localisation of the stem cells is not the same during stable conditions as after transplantation. These observations suggest a new type of niche, called reconstituting stem cell niches, which has never been proposed before," said Dr Bonnet.

The calvarium is a thin flat bone on top of the skull and is the only place where it's possible to carry out non-invasive high resolution imaging of the bone marrow within intact bones. Although this bone has significant differences compared with leg bones, the researchers demonstrated that HSCs and stem cell niches in the calvarium are fully functional. Dr Bonnet added: "This validates our approach and provides a new imaging strategy to study the biology of HSCs, leukaemic stem cells and their interactions with the bone marrow microenvironment."

She concluded: "The information generated improves our collective knowledge and understanding on the bone marrow microenvironment structure and function. Such approaches will be very helpful to analyse what is happening in the context of leukaemia and cancer spread to the bones, as well as to image the distribution of drugs in the body and to assess their effectiveness.

"Enabling us to study how chemotherapy affects the bone marrow environment will allow the design of new drugs that are less toxic for normal cells and drugs that can selectively target specific cell types in the bone marrow, such as the cancer cells."

The paper, Multimodal imaging reveals structural and functional heterogeneity in different bone marrow compartments: functional implications on hematopoietic stem cells, is published in Blood.

  • New knowledge about haematopoietic stem cells (HSCs) from Cancer Research UK's London Research Institute is hoped to lead to more targeted and less toxic leukaemia and bone cancer drugs. 
  • Stem cells are immature cells that have not yet developed into the specialised cells that make up our organs and tissues. They also have the ability to "self-renew", or make identical copies of themselves, almost indefinitely. 
  • HSCs are found in the bone marrow and generate all the different types of mature blood cells.