A theoretical simulation of hematopoietic stem cells during oxygen fluctuations: prediction of bone marrow responses during hemorrhagic shock.

The bone marrow (BM) responds to various diseases, including infections and hemorrhagic shock, by generating immune and blood cells. These cells are derived from a finite number of lymphohematopoietic stem cells (LHSC) close to the endosteal region of the BM. This study presumes that studies on LHSC involving proteomics, computational biology, and genomics could be aided by mathematical models. A theoretical model is developed to predict the responses of proliferating (P) nonproliferating (N) BM cells during acute blood loss when the Po2 in the BM is decreased. Hematopoietic responses were simulated for otherwise healthy individuals who have been subjected to various degrees of blood loss, as represented by 3%, 5%, and 20% O2. The model is robust and could predict hematopoietic activity in the area close to the endosteum during low Po2 as for acute blood loss. Steady-state hematopoiesis at oxygen saturation (80%) in healthy individuals could not be simulated with the equations. Functional assays tested the model with an in vitro assay of the most primitive LHSC (modified long-term culture-initiating cell assay, LTC-IC). The LTC-IC assay showed that 1%, 3% - 5%, and 20% O2 mediate significant increases in the proliferation of the most primitive BM progenitors, as compared with 80% O2. Thus, the functional studies show that the theoretical model is robust and could be used to gain insights into the biology of LHSC during different degrees of blood loss. The utility of such a model in surgical trauma is discussed.