Bone marrow function following chemotherapy

Bone Marrow Function Following Chemotherapy

A critical element of patient outcome following bone marrow transplantation is efficient recovery of hematopoiesis. We have a long standing interest in understanding the influence of aggressive chemotherapy, often used clinically prior to transplant, on a patient's bone marrow capacity to support this recovery. We have identified disruption of stromal and osteoblast expression of VCAM-1, CXCL-12, and a variety of other factors required for either stem cell or committed progenitor cell chemotaxis, survival, and differentiation. These disruptions have various upstream causes including deregulation of p65 influencing VCAM-1 expression and activation of MMP-2 by chemotherapy resulting in cleavage of CXCL-12 chemokine. We have also described increased levels of bioavailable TGF-beta subsesequent to stromal cell exposure to specific chemotherapeutic agents, with neutralization of TGF-beta restoring the ability of treated stromal cell to support pro-B cell survival and expansion. We are increasingly focused on the damage that may result in reduced microenvironment support of hematopoietic stem cells and current models include both murine and human cells for ongoing work. This work is currently supported by the Heart, Lung, and Blood Institute of the NIH.


Illustration of primary cells in the "hematopoietic spaces" with the bone marrow microenvironment.
This illustrates the primary cells that constitute the bone marrow microenvironment located within the “hematopoietic spaces”. The interactions between hematopoietic cells and stromal cells are crucial for normal hematopoiesis to occur. It has been demonstrated in vitro that cloned stromal cell monolayers are able to maintain both lymphopoiesis and myelopoiesis while other bone marrow cell types are not able to support either, and while other cells in the hematopoietic microenvironment may have some functional roles in influencing hematopoiesis, bone marrow stromal cells are a critical element.