Potential Osteoinductive Effects of Hydroxyapatite Nanoparticles on Mesenchymal Stem Cells by Endothelial Cell Interaction

Abstract

Nano-hydroxyapatite (nano-HA) has attracted substantial attention in the field of regenerative medicine. Endothelial cell (EC)-mesenchymal stem cell (MSC) interactions are necessary for bone reconstruction, but the manner in which nano-HA interacts in this process remains unknown. Herein, we investigated the cytotoxicity and osteoinductive effects of HA nanoparticles (HANPs) on MSCs using an indirect co-culture model mediated by ECs and highlighted the underlying mechanisms. It was found that at a subcytotoxic dose, HANPs increased the viability and expression of osteoblast genes, as well as mineralized nodules and alkaline phosphatase production of MSCs. These phenomena relied on HIF-1α secreted by ECs, which triggered the ERK1/2 signaling cascade. In addition, a two-stage cell-lineage mathematical model was established to quantitatively analyze the impact of HIF-1α on the osteogenic differentiation of MSCs. It demonstrated that HIF-1α exerted a dose-dependent stimulatory effect on the osteogenic differentiation rate of MSCs up to 1500 pg/mL, which was in agreement with the above results. Our data implied that cooperative interactions between HANPs, ECs, and MSCs likely serve to stimulate bone regeneration. Furthermore, the two-stage cell-lineage model is helpful in vitro system for assessing the potential influence of effector molecules in bone tissue engineering.

Spatiotemporal correlation between HIF ‐1α and bone regeneration

“…It has been demonstrated that HIF‐1α can induce the transformation of bone marrow stem cells into osteoblasts 55,56 . Researchers 57 found that hypoxia‐induced HIF‐1α promotes osteoblast expression of BMP‐2 and promotes new osteogenesis by synergizing with the ILK/Akt/mTOR signaling pathway.…”

“…has been demonstrated that HIF-1α can induce the transformation of bone marrow stem cells into osteoblasts. 55,56 Researchers 57 found that hypoxia-induced HIF-1α promotes osteoblast expression of BMP-2 and promotes new osteogenesis by synergizing with the ILK/Akt/ mTOR signaling pathway. Patients with postmenopausal osteoporosis have abnormal proliferation of adipose tissue within the bone marrow 58,59 and decreased bone regenerative capacity.…”

Effect of Injectable Platelet-Rich Fibrin with a Nano-Hydroxyapatite Bone Graft on the Treatment of a Grade II Furcation Defect

“…Along with the growth factors, a number of leucocytes may also be present in the i-PRF which might have an anti-inflammatory effect [ 41 ] thus aiding in better healing of the tissues. (Abd El Raouf et al, 2019) [ 42 ] Along with nano-HA bone graft, i-PRF can have an osteoinductive effect on the neighbouring cells due to the release of growth factors and bone morphogenetic proteins [ 43 , 44 ]. Hence, the nano-HA crystalline bone graft showed better comparable results when used with i-PRF.…”

HIF-1α Regulates Bone Homeostasis and Angiogenesis, Participating in the Occurrence of Bone Metabolic Diseases

“…Hydroxyapatite (HA), as a commonly used inorganic biomaterial, loaded with co-overexpressed osteogenic factor semaphoring 3A (Sema3A) and HIF-1α modified MSCs, promotes osteogenic differentiation [ 178 , 179 ]. Furthermore, Nano-HA stimulates ECs to produce HIF-1α dose-dependently and upregulate osteogenic genes via the ERK1/2 signal pathway, increasing mineralized nodules and ALP [ 180 ]. Cu-Li-doped Nano-HA (Cu-Li-nHA) upregulates HIF-1α and stromal cell-derived factor-1 (SDF-1) by steadily releasing Cu 2+ , then promotes angiogenesis and induces BMSCs homing to necrotic areas, stimulating BMSCs to differentiate into osteoblasts through Wnt/GSK-3β/β-catenin pathway [ 181 , 182 , 183 ].…”