Cytopenias are a major risk factor particularly thrombocytopenia in HIV infection, heart disease, and cancer. Hematopoietic abnormalities such as its inhibition leads to, or cause, multiple cytopenias in HIV infected individuals with thrombocytopenia emerging as a major risk factor for morbidity and mortality and even more so in patients also suffering from heart conditions. Thrombocytopenia is also a major risk factor in cancer patients undergoing chemotherapy. In HIV infected patients, cytopenias are not just caused by infection but are also induced due to prolonged antiretroviral therapy and thus can play a synergistic role. We will investigate herein the mechanisms of inhibition of stem cell differentiation into hematopoietic lineages in vivo.
The mechanisms of hematopoietic inhibition are poorly understood. We use the severe combined immunodeficient mouse cotransplanted with human fetal thymus and liver tissues (SCID-hu) wherein this conjoint hematopoietic organ that develops, to investigate the mechanisms and therapies for inhibition of stem cell differentiation. We have previously shown using this model system that HIV-1 infection inhibits multilineage CD34+ hematopoietic progenitor stem cell differentiation in an indirect manner independent of infection of CD34+ cells in vivo. Furthermore, as a therapeutic strategy this SCID-hu reconstitution model system offers the utilization of either CD34+ cells or even their precursor embryonic stem cells to provide a continuing source of the HSC for alleviation of chronic cytopenias in affected patients. It is hoped that the expected enhancement of stem cell differentiation into multilineage hematopoiesis will aid in decrease of cytopenias in general and thrombocytopenia in particular, in heart disease and cancer therapy.
This model system is also adapted for systemic reconstitution of the stem cells for self-renewal and differentiation to overcome cytopenias. The model will also be tested for the first time to determine if the embryonic stem cell lines such as H1 or H9 will spontaneously or in a directed manner, differentiate into hematopoietic lineages in vivo. In such an event, a greater supply of hematopoietic progenitors will be available to combat cytopenias in vivo. Thus this project involves a combination of mechanistic and therapeutic studies on cytopenias arising from inhibition of stem cell differentiation in vivo.
Statement of Benefit to California:
The loss of cells in blood (cytopenias) traces their origin to stem cells. This is a general undesirable clinical phenomenon that occurs in various parts of the world including United States either due to natural bodily abnormalities arising from environmental hazards, or from clinical therapies. It has recently been reported in the local newspaper (The San Diego Union-Tribune) that anemia is widely prevalent in San Diego and attributable to environmental factors or causes. Moreover, large cities in California such as San Francisco and Los Angeles have high incidence of HIV infection and both infection and the drugs used in their antiretroviral therapies cause anemia, leucopenia, granulocytopenia and other cytopenias.
Thus for undetermined environmental reasons, the inhabitants of San Diego are vulnerable at least one of the cytopenias, anemia, loss of red blood cells or erythrocytes and hence decreased binding of hemoglobin or availability of iron stores. Cytopenias are a major risk for morbidity and mortality which is particularly the case with thrombocytopenia as it occurs in heart disease. Patients undergoing heart surgery are highly vulnerable to mortality due to thrombocytopenia.
Therefore the studies that we propose are highly beneficial to addressing some of these pressing health issues of California. While certain forms of cytopenias may respond to simpler therapies, it is not clear if the therapy or drug(s) usage can be temporary. Chronic cytopenias may require prolonged or sustained therapeutic interventions and this can be a complicating factor if the patient is also suffering from other clinical conditions. In an extreme case, this complicating factor can even be HIV infection and contributing to greater risk of cytopenias. Or else, it can be a malignancy and that even requires treatment for neutropenia while undergoing autologous stem cell transplantation.
Success in this investigation can produce tremendous benefits to patients suffering from chronic or acute cytopenias and can be life saving in treatments and surgeries or transplantation. Understanding the mechanisms of cytopenias that occur under different conditions will help develop therapies that are tailored to the mode of induction of cytopenias in an individual. We strongly believe that since the origins of cytopenias lie in stem cells so do their therapies.