LAUSR

Studying bone marrow hematopoiesis has provided insights into how heterologous cells interrelate to dynamically regulate production of mature effector cells. The interactions that have been defined have largely been at the level of receptor proteins and signaling pathways that are common among mammalian tissues but are likely to be late in evolutionary time. We hypothesized that organized complex tissues like bone marrow also retain primitive means of communicating from early metazoan ancestors. Multicellular life must have developed simple sensing and communication methods to coordinate responses to alterations in their microenvironment. These are likely to be rapid and non-redundant with subsequent, more complex processes. We considered it likely that these primitive mechanisms remain and may participant in stress and disease states. Evaluating bone marrow hematopoiesis with attention to possible evolutionarily primitive processes, we defined two scenarios. First, a small non-coding RNA based method of rapidly altering adjacent cell protein translation and proliferation that is based on vesicular exchange of cytoplasmic contents. This occurs between select stromal and hematopoietic cells and appears to be responsive to stress. Second, we found that proton partitioning across the cell membrane affects anabolic metabolism to enhance cell proliferation. This is accomplished in normal hematopoietic cells largely secondary to lactate production and mass action in settings of nutrient abundance. However, epigenetic alterations at specific sites affects intracellular shifts of pH in malignant myeloid cells that enforces a metabolic alteration sufficient to provide cells a competitive growth advantage. The bone marrow therefore includes a broad repertoire of strategies to modulate hematopoiesis that extend well beyond defined cytokine and chemokine pathways. These may be responsive to stress conditions or be coopted in settings of disease and may offer new targets for therapeutics.