Differential functional roles of fibroblasts and pericytes in the formation of tissue-engineered microvascular networks in vitro

Abstract

Formation of a perfusable microvascular network (μVN) is critical for tissue engineering of solid organs. Stromal cells can support endothelial cell (EC) self-assembly into a μVN, but distinct stromal cell populations may play different roles in this process. Here we describe the differential effects that two widely used stromal cell populations, fibroblasts (FBs) and pericytes (PCs), have on μVN formation. We examined the effects of adding defined stromal cell populations on the self-assembly of ECs derived from human endothelial colony forming cells (ECFCs) into perfusable μVNs in fibrin gels cast within a microfluidic chamber. ECs alone failed to fully assemble a perfusable μVN. Human lung FBs stimulated the formation of EC-lined μVNs within microfluidic devices. RNA-seq analysis suggested that FBs produce high levels of hepatocyte growth factor (HGF). Addition of recombinant HGF improved while the c-MET inhibitor, Capmatinib (INCB28060), reduced μVN formation within devices. Human placental PCs could not substitute for FBs, but in the presence of FBs, PCs closely associated with ECs, formed a common basement membrane, extended microfilaments intercellularly, and reduced microvessel diameters. Different stromal cell types provide different functions in microvessel assembly by ECs. FBs support μVN formation by providing paracrine growth factors whereas PCs directly interact with ECs to modify microvascular morphology.

Clinical Application of Bone Marrow Mesenchymal Stem/Stromal Cells to Repair Skeletal Tissue

“…CXCL12 has also been reported to promote early vascular formation when co-administered with MSC, which was equivalent to MSC co-administration of endothelial progenitor cells [ 114 ]. In contrast, the Food and Drug Administration (FDA) approved C-X-C chemokine receptor type 4 (CXCR4) antagonist, AMD3100, also activates MSC mobilization within the circulation, which assisted in femoral and spinal bone regeneration [ 115 , 116 ]. These observations suggest that CXCL12 can be utilized in multiple ways to help facilitate MSC mediated bone regeneration.…”

Current Strategies for the Regeneration of Skeletal Muscle Tissue

“…SCs are sensitive to their surrounding niche, which consists of several cell types, including fibroblasts, endothelial cells, immune cells, and inflammatory cells. These cells have been shown to mediate the proliferation and differentiation of SCs [ 29 , 30 ]. In particular, it has been reported that fibroblasts significantly modulate the SC niche and that after injury, the absence of fibroblasts can lead to the formation of smaller regenerated fibers [ 29 ].…”

“…iPSCs can be generated in vitro by introducing reprogramming factors, known as Yamanaka factors, into somatic cells. They possess unlimited self-renewal capacity in culture and can be differentiated into almost all cell types [ 30 , 101 ]. Thus, iPSCs offer an attractive option for myogenic regeneration due to their ability to differentiate into myogenic cells [ 19 , 102 ].…”

The Intrinsic Cardiac Nervous System and Its Role in Cardiac Pacemaking and Conduction

“…Another factor affecting adrenergic-cholinergic balance is the upregulation of the neural-crest derived ICA cells, which, however, has only been reported so far in mice [ 22 ]. Given the partial innervation after heart transplantation and the resulting abnormal sympathetic-parasympathetic balance, promoting cardiac innervation opens up a research scope for tissue engineering, e.g., triggering neo-innervation before heart transplantation or prior to implantation [ 216 ].…”