Regeneration of Three Layers Vascular Wall by using BMP2-Treated MSC Involving HIF-1α and Id1 Expressions Through JAK/STAT Pathways

Abstract

Engineering living, multilayered blood vessels to form in vivo arteries is a promising alternative to peripheral artery bypass using acellular grafts restricted by thrombosis and occlusion at long term. Bone Morphogenetic Protein 2 (BMP2) is a growth factor determining in the early vascular embryonic development. The aim of the present study was evaluate the collaborative effect of recombinant human--BMP2 and Bone marrow--Mesenchymal stem cells (BM-MSCs) seeded on vascular patch to regenerate a vascular arterial wall in a rat model. BM-MSCs expressing green fluorescent protein (GFP) seeded on vascular patch were cultured in presence of recombinant human-BMP2 [100 ng/mL] during 1 week before their implantation on the abdominal aorta of Wistar rats. We observed after 2 weeks under physiological arterial flow a regeneration of a three layers adult-like arterial wall with a middle layer expressing smooth muscle proteins and a border layer expressing endothelial marker. In vitro study, using Matrigel assay and co-culture of BM-MSCs with endothelial cells demonstrated that rh-BMP2 promoted tube-like formation even at long term (90 days) allowing the organization of thick rails. We demonstrated using inhibitors and siRNAs that rh-BMP2 enhanced the expression of HIF-1α and Id1 through, at least in part, the stimulation of JAK2/STAT3/STAT5 signaling pathways. Rh-BMP2 by mimicking embryological conditions allowed vascular BM-MSCs differentiation.

Network-Based Method for Identifying Co-Regeneration Genes in Bone, Dentin, Nerve and Vessel Tissues

“…JAK2 (ENSP00000371067), as a specific protein tyrosine kinase encoding gene, has been generally reported to involve in various cytokine receptor associated biological processes [67,68]. In 2011, a review [69] on the genetic contribution on the regeneration of vascular walls confirmed that JAK/STAT pathway which JAK2 directly participate in the vessel regeneration processes around the bone tissue, confirming our inference. As for its specific functions during bone regeneration, 4-methoxydalbergione, as a functional chemical, has been reported to suppress the growth and regeneration of human osteoblast proliferation and differentiation by down-regulating JAK2/STAT3 pathway, validating the potential role of JAK2 during the regeneration of bone [70].…”

Rebuilding the Damaged Heart: Mesenchymal Stem Cells, Cell-Based Therapy, and Engineered Heart Tissue

“…Interestingly, subpopulations of MSCs that highly express CD146 are strongly associated with lineage commitment towards vascular smooth muscle cells (93). Using a murine model, investigators were able to regenerate all three layers of the vascular wall by induction of MSCs together with recombinant human-BMP-2 (rh-BMP-2) seeded on a vascular patch, which promoted tubelike formation 90 days following aortic implantation (25). fluxes, potassium-induced calcium fluxes, and express ␤-myosin heavy chain and desmin (400).…”

Signals Between Cells and Matrix Mediate Bone Regeneration

“…The expression of these markers serves to ascertain osteoblastic differentiation and evaluate the progression of bone formation. Unfortunately, at present, clear markers to identify and isolate mesenchymal stem cells or osteoprogenitors are not available and the lack of hematopoietic stem cells markers, as well as cellular morphological characteristics, such as undeveloped cytoplasmic structure, are the only reliable criteria for osteoprogenitors (Belmokhtar et al 2011;Bernardo et al 2011;Vater et al 2011).…”

“…Transient transfection and conditional expression approaches achieved in mice and other animals, thorough adeno and lentiviral, as well as non-viral, approaches such as electroporation (Franceschi et al 2000;Holstein et al 2009;Kawai et al 2006). Gene delivery approaches being used in an ex vivo and in vivo gene delivery can also be utilized in humans to deliver genes to marrow stromal cells (Belmokhtar et al 2011;Chen et al 2011). Expression control modifications at embryo through transgenic animals or conditional modifications which, dependent on the initiator or temporary gene alteration in adult animals, assist in determining the relative importance of cell, matrix or inducer molecules to mineralized tissue healing.…”