Helping to Provide Better Outcomes for Hematopoietic Stem Cell Transplantations

Richard Mollard MBA, PhD*

Bone marrow transplantation involves replacing hematopoietic stem cells found within the bone marrow of a patient with a potentially lethal disease of the blood system with hematopoietic stem cells from a healthy person with no disease. Success of this procedure relies on several factors. The immune system of the patient and the donor must be a close match. If they are not, the new immune system could attack the recipient’s body. It is also critical that the engraftment of the new hematopoietic stem cells be durable, so that it lasts for the life of the recipient, and rapid, so that the blood system can be restored as fast as possible. If engraftment takes a long time and not enough white blood cells are present to fight threatening bacterial and fungal infections, the patient can become very ill and the transplant can be compromised.

One innovation in the field of hematopoietic stem cell transplantation has been the use of cord blood as a source of stem cells. Cord blood is now preferred over bone marrow by some clinicians for several reasons. Cord blood is easily obtained and causes no harm or pain to the donor, the chances of the stem cells from cord blood being contaminated with viruses and bacteria is lower, and a lower degree of immune matching between the donor cord blood and recipient patient is generally required for a successful outcome.

One problem with cord blood as a source of stem cells, however, is that the number of stem cells that can be obtained is often too low for the transplant to succeed. Researchers have therefore turned to investigating methods to increase the number of stem cells in a given batch. In a recent report, Delaney and colleagues demonstrated some advanced success in expanding cord blood hematopoietic stem cells (1). They found that by activating a signalling system in isolated human cord blood hematopoietic stem cells, called the Notch molecular signalling system, the number of hematopoietic stem cells could be expanded by more than 100 fold in a relatively short time frame. Interestingly, a separate report published by Butler and colleagues showed that activation the Notch signalling system occurs naturally in the body to help expand the hematopoietic stem cell pool (2). Delaney and colleagues next transplanted the expanded human hematopoietic stem cells into mice. Importantly, the cells not only showed promise for long term engraftment and an ability to contribute to all recognized important cell types of the immune system, they also significantly reduced the time of engraftment.

Next, Delaney and colleagues instigated a clinical study involving ten volunteers with high-risk acute leukaemia. A double batch of cord blood was simultaneously transplanted into each patient: one unexpanded and one expanded by activating the Notch signalling system. The clinical studied aimed to cure the patients while examining: the safety of injecting the expanded stem cells, the speed of engraftment of the expanded stem cells and their associated ability to quickly fight off infections and the durability of the expanded stem cells’ engraftment. Although only a small number of patients were tested, transplantation of expanded cells was recognised to be safe and both unexpanded and expanded batches contributed to engraftment times quicker than those previously reported for double batches of unexpanded cord transplants. Accordingly, the time to reconstitute the immune system was more than halved, which means these patients should be better at fighting off infections.

Longer term follow-up of a larger number of patients transplanted with Notch treated cells, however, is still required to reliably assess the durability of engraftment. Together with further work identifying other molecules that act naturally in the body to expand hematopoietic stem cells, the further development of better therapies for patients with a wide range of blood diseases appears promising.

*Author Affiliation
Richard Mollard, MBA, PhD
The Department of Biochemistry and Molecular Biology
Monash University
Clayton 3800
Australia

Notes:

1. Delaney C., Heimfeld S., Brashem-Stein C., Voorhies H., Manger R.L., Bernstein I.D. (2010). Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. Nat Med. 16(2), 232-236.

Posted August 27, 2010