Abstract
Late-term complications of hematopoietic cell transplantation (HCT) are numerous and include incomplete engraftment. One possible mechanism of incomplete engraftment after HCT is cytokine-mediated suppression or dysfunction of the bone marrow microenvironment. Mesenchymal stromal cells (MSCs) elaborate cytokines that nurture or stimulate the marrow microenvironment by several mechanisms. We hypothesize that the administration of exogenous MSCs may modulate the bone marrow milieu and improve peripheral blood count recovery in the setting of incomplete engraftment. In the current study, we demonstrated that posttransplant intramuscular administration of human placental derived mesenchymal-like adherent stromal cells [PLacental eXpanded (PLX)-R18] harvested from a three-dimensional in vitro culture system improved posttransplant engraftment of human immune compartment in an immune-deficient murine transplantation model. As measured by the percentage of CD45+ cell recovery, we observed improvement in the peripheral blood counts at weeks 6 (8.4 vs. 24.1%, p < 0.001) and 8 (7.3 vs. 13.1%, p < 0.05) and in the bone marrow at week 8 (28 vs. 40.0%, p < 0.01) in the PLX-R18 cohort. As measured by percentage of CD19+ cell recovery, there was improvement at weeks 6 (12.6 vs. 3.8%) and 8 (10.1 vs. 4.1%). These results suggest that PLX-R18 may have a therapeutic role in improving incomplete engraftment after HCT.
Highlights
The late-term complications of hematopoietic cell transplantation (HCT) are numerous and include, but are not limited to, chronic graft-vs.-host disease, immunodeficiency, opporunistic infections, liver, pulmonary, and endocrine dysfunction, gonadal failure, and secondary malignancy [1, 2]
It is possible that administration of mesenchymal stromal cells (MSCs) in the setting of incomplete or delayed engraftment can modulate the milieu of the bone marrow microenvironment, through both direct interaction with hematopoietic stem cells (HSCs) and through secretion of cytokines, to improve blood counts posttransplant [25–27]
Because there is no mouse model of delayed or incomplete engraftment, we proposed to administer PLacental eXpanded (PLX)-R18 posttransplant in a well-established murine model of transplant utilizing sub-optimal doses of human CD34-selected umbilical cord blood (UCB) after radiation conditioning
Summary
The late-term complications of hematopoietic cell transplantation (HCT) are numerous and include, but are not limited to, chronic graft-vs.-host disease (cGVHD), immunodeficiency, opporunistic infections, liver, pulmonary, and endocrine dysfunction, gonadal failure, and secondary malignancy [1, 2]. Cytopenia may be related to transplant specific complications, such as cGVHD, inadequate cell dose of the graft, marrow dysfunction, immunosuppressive medications, and late chemotherapeutic effects [11, 12]. Possible mechanisms of cytopenia after HCT include cytokine-mediated suppression of megakaryopoiesis, erythropoiesis, or lymphopoiesis, and dysfunction of the bone marrow microenvironment [16, 17]. It is possible that administration of MSCs in the setting of incomplete or delayed engraftment can modulate the milieu of the bone marrow microenvironment, through both direct interaction with hematopoietic stem cells (HSCs) and through secretion of cytokines, to improve blood counts posttransplant [25–27]
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