Improving bone marrow transplantation outcomes via enhancement of recipient bone marrow macrophages

Project type/s Basic Science
Project status Currently underway

Using bone marrow stem cell transplantation to treat blood cancer and other diseases has considerable risk and limitations. This results in either inability to proceed to having a transplant, often leaving the patient with no other treatment options, or, when transplant has occurred, significant complications and even death. For this potentially curative therapy to reach its full potential we need to discover and develop ways to make it safer. This research program is focused on finding ways to make the transplant recipient's bone marrow environment more resilient to the damage that occurs during the harsh treatments needed to prepare a patient for transplant and therefore more able to support acceptance and establishment of donate blood stem cells. We have identified a specific cell in the recipient's bone marrow that plays an essential role in accepting and supporting the donated blood stem cells. We are now applying this basic biomedical discovery to developing ways to increase the resilience of these cells in the recipient and enhance their ability to support and accelerate recovery from bone marrow transplantation. This research also has wider implications for reducing the undesired bone marrow damage that occurs during chemotherapy treatment for cancer, and consequently making chemotherapy treatment for a large number of different cancer types safer.

Team Members

Current Student Opportunities

Project 1 Description
Demonstrate that resilience and long term persistence of recipient BM resident Macrophages is a common tissue protective mechanism in clinically relevant cytotoxic treatments and transplantation models.
Our published data demonstrates that resilience and persistence of recipient resident macrophages is essential for successful transplantation. These outcomes are based upon the pre-transplantation myeloablation strategy, total body irradiation, that is not commonly applied in the clinical setting. In this project, we will characterise the resilience and persistence of resident bone marrow macrophages after clinically-relevant chemotherapy or combination chemotherapy plus radiation-based pre-transplant myeloablation. This strategy will also determine whether recipient resident macrophages persist in the more complex scenario of allogeneic transplantation. This research aims to develop novel approaches to improve resilience to chemotherapy and improve recovery from bone marrow transplantation, making both clinical therapies safer.

Project 2 Description
Determine if recipient macrophages are essential to transplantation success in the early post-transplant period.
Resilience and persistence of recipient resident bone marrow macrophages is essential for successful transplantation outcomes; however, our preliminary data suggests that these cells are also critical to stem cell engraftment. This project will investigate the impact of recipient macrophage depletion in the early post-transplant period (first 4 weeks post-transplant) on donor stem cell engraftment using multiple in vivo models of macrophage depletion. The aim of this research project is to discovery novel therapeutic targets to promote bone marrow recovery after transplantation, thus improving the safety of the potentially curative treatment strategy.

Project 3 Description
In situ characterisation of tissue macrophage repopulation kinetics following bone marrow transplantation.
Recent experimental evidence has identified that certain macrophage populations undergo replacement via self-renewal instead of, replenishment by differentiating monocyte precursors. In this project we will use two transgenic mice strains that express different fluorescent markers in their macrophages (MacApple and MacGreen mice) in a bone marrow transplantation model to distinguish in which tissues do macrophage populations regenerate via self-renewal or via monocyte recruitment, or via a combination of both regeneration strategies.

Techniques you will learn in our group will include:
Animal handling techniques: including injections, total body irradiation, chemotherapy and stem cell transplantation.
Imaging: Immunohistochemistry and fluorescent imaging of tissue sections, whole-mounted tissues and intravital live imaging.
Flow cytometry: analysis of surface and intracellular markers of HSC and macrophage populations in various tissues.

Positions available for:
Honours Student

Contact Person: A/Prof Allison Pettit (PhD)