Blood Flow Regulates Metabolism in Hematopoietic Development

Blood flow modifies oxygen availability and biomechanical forces within the vasculature of the embryo as the hematopoietic system develops. The aorta-gonad-mesonephros (AGM) envelops the largest artery in the body and is a critical site for the emergence of hematopoietic stem cells (HSCs). Herein, I discuss the role of hypoxia-inducible factors (HIFs) and force as determinants of metabolism and fate determination. To address the effects of blood flow on hematopoietic development, I employ mouse embryo models and biomimetic culture. Real-time cell metabolic analyses show that oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) are altered by flow in cultures of AGM cells. Additionally, mitochondrial permeability transition pore (mPTP) activity assays indicate that mPTP opening is regulated as precursors commit to a hematopoietic fate. Moreover, transcriptome data suggest that expression of Ppif, the gene that encodes the mPTP regulator Cyclophilin D, may be downregulated by fluid force. Together, these data implicate blood flow in regulation of metabolic activity in the AGM region, influencing bioenergetics and serving as a cue for HSC emergence. The broader significance of this research lies in its potential to accurately recapitulate the hematopoietic niche in vitro for study of blood disorders and improvement of cellular therapies.