Biology subjects

Xia, I. F.

Publications and source records attributed to Xia, I. F..

3 recordsLinked to original sources

bioRxiv2026

A mitochondrial program encodes brain vascular reserve

Brain resilience depends on collateral vessels whose geometries preserve blood flow when primary arteries are perturbed. How these protective vascular architectures are developmentally established remains unknown. Using longitudinal in vivo imaging in zebrafish, we show that mitochondrial state in embryonic angiogenic tip cells encodes the topology of basal and surface brain collateral networks. Mechanistically, microRNA-125a establishes the bioenergetic and redox balance of endothelial tip-cell mitochondria through conserved repression of the metabolic regulator PGC1a. Disruption of the microRNA-125a-PGC1a axis uncouples mitochondrial capacity from redox buffering in developing brain tip cells, redirecting their migration toward sparse, incompletely connected collateral network topologies and increasing adult cerebrovascular vulnerability. Consistent with this mechanism, humans with subclinical cerebrovascular injury exhibit reduced circulating microRNA-125a levels associated with incomplete basal collateral configurations. Together, these findings identify mitochondrial state as an instructive and conserved developmental program that encodes brain vascular reserve.

developmental biology↗

bioRxiv2023

Hemodynamics regulate spatiotemporal artery muscularization in the developing circle of Willis

Vascular smooth muscle cells (VSMCs) envelop vertebrate brain arteries, playing a crucial role in regulating cerebral blood flow and neurovascular coupling. The dedifferentiation of VSMCs is implicated in cerebrovascular diseases and neurodegeneration. Despite its importance, the process of VSMC differentiation on brain arteries during development remains inadequately characterized. Understanding this process could aid in reprogramming and regenerating differentiated VSMCs in cerebrovascular diseases. In this study, we investigated VSMC differentiation on the zebrafish circle of Willis (CoW), comprising major arteries that supply blood to the vertebrate brain. We observed that the arterial expression of CoW endothelial cells (ECs) occurs after their migration from the cranial venous plexus to form CoW arteries. Subsequently, acta2+ VSMCs differentiate from pdgfrb+ mural cell progenitors upon recruitment to CoW arteries. The progression of VSMC differentiation exhibits a spatiotemporal pattern, advancing from anterior to posterior CoW arteries. Analysis of blood flow suggests that earlier VSMC differentiation in anterior CoW arteries correlates with higher red blood cell velocity wall shear stress. Furthermore, pulsatile blood flow is required for differentiation of human brain pdgfrb+ mural cells into VSMCs as well as VSMC differentiation on zebrafish CoW arteries. Consistently, the flow-responsive transcription factor klf2a is activated in ECs of CoW arteries prior to VSMC differentiation, and klf2a knockdown delays VSMC differentiation on anterior CoW arteries. In summary, our findings highlight the role of blood flow activation of endothelial klf2a as a mechanism regulating the initial VSMC differentiation on vertebrate brain arteries.

developmental biology↗

bioRxiv2022

Hematopoietic stem and progenitor cell heterogeneity is inherited from the embryonic hemogenic endothelium

Multipotent hematopoietic stem/progenitor cells (HSPCs) generate all mature blood cells in the erythroid, lymphoid, and myeloid lineages. HSPCs are initially produced in the embryo, via transdifferentiation of hemogenic endothelial cells (hemECs) in the aorta-gonad mesonephros (AGM). HSPCs in the AGM are functionally heterogenous in differentiation and proliferative output, but how these intrinsic differences are acquired remains unanswered. This knowledge could inform approaches to overcome the dysregulation of HSPC heterogeneity associated with poor outcomes of autologous transplants. Here we discovered that loss of microRNA (miR)-128 (miR-128{Delta}/{Delta}) in zebrafish leads to an expansion of hemECs forming replicative HSPCs in the AGM, and a skew towards the erythroid and lymphoid lineages in larval and adult stages. Furthermore, we found that inhibiting miR-128 during the differentiation of human pluripotent stem cells into hemECs, but not during the endothelial-to-hematopoietic transition, recapitulated the lineage skewing. In vivo, expression of wild-type miR-128 in endothelium restored the blood lineage distribution in miR-128{Delta}/{Delta} zebrafish. We found that miR-128 represses the expression of the Wnt inhibitor csnk1a1 and the Notch ligand jag1b, and thus promotes Wnt and Notch signaling in hemECs. De-repression of cskn1a1 resulted in hemECs generating replicative and erythroid-biased HSPCs, whereas de-repression of jag1b resulted in hemECs forming lymphoid-biased HSPCs in the AGM and relative mature blood cells in adult. We propose that HSPC heterogeneity is established in hemogenic endothelium prior to transdifferentiation and is programmed in part by Wnt and Notch signaling modulation.

developmental biology↗