Human NELL1 Protein Augments Constructive Tissue Remodeling with Biologic Scaffolds

Abstract

Biologic scaffolds composed of extracellular matrix (ECM) derived from decellularized tissues effectively reprogram key stages of the mammalian response to injury, altering the wound microenvironment from one that promotes scar tissue formation to one that stimulates constructive and functional tissue remodeling. In contrast, engineered scaffolds, composed of purified ECM components such as collagen, lack the complex ultrastructure and composition of intact ECM and may promote wound healing but lack factors that facilitate constructive and functional tissue remodeling. The objective of the present study was to test the hypothesis that addition of NELL1, a signaling protein that controls cell growth and differentiation, enhances the constructive tissue remodeling of a purified collagen scaffold. An abdominal wall defect model in the rat of 1.5-cm² partial thickness was used to compare the constructive remodeling of a bovine type I collagen scaffold to a biologic scaffold derived from small intestinal submucosa (SIS)-ECM with and without augmentation with 17 μg NELL1 protein. Samples were evaluated histologically at 14 days and 4 months. The contractile response of the defect site was also evaluated at 4 months. Addition of NELL1 protein improved the constructive remodeling of collagen scaffolds but not SIS-ECM scaffolds. Results showed an increase in the contractile force of the remodeled skeletal muscle and a fast:slow muscle composition similar to native tissue in the collagen-treated group. The already robust remodeling response to SIS-ECM was not enhanced by NELL1 at the dose tested. These findings suggest that NELL1 protein does contribute to the enhanced constructive remodeling of skeletal muscle.

Neural EGF-like protein 1 (NELL-1): Signaling crosstalk in mesenchymal stem cells and applications in regenerative medicine

“…Previous groups have attached NELL-1 to a biologic scaffold and found that the addition of the protein augmented the constructive remodeling of the tissue. 132 The modification of PPCN with NELL-1 may provide an extremely effective method for the growth of new bone in an injectable form. Such combinations of scaffold materials and NELL-1 should be particularly useful for craniofacial defect repair ( Fig.…”

Neural epidermal growth factor-like 1 protein variant increases survival and modulates the inflammatory and immune responses in human ACE-2 transgenic mice infected with SARS-CoV-2

“…20,21 NELL1 is a naturally occurring secreted signaling molecule that mediates tissue growth and maturation during fetal development and stimulates healing in skin, muscle, bone, heart and cartilage after acute injury and systemic diseases such as osteoporosis and osteoarthritis. [29][30][31][32][33][34][35][36][37][38] It is essential during the development of epithelial linings of esophagus, gastrointestinal tract and respiratory system. [39][40][41] Fifteen years of basic science research on NELL1 biology demonstrate that exogenous NELL1 has strong anti-inflammatory and pro-tissue healing effects in the skin, muscle, cartilage, and bone ( Table 1).…”

“…[39][40][41] Fifteen years of basic science research on NELL1 biology demonstrate that exogenous NELL1 has strong anti-inflammatory and pro-tissue healing effects in the skin, muscle, cartilage, and bone ( Table 1). [31][32][33][34][35][36][37][38][41][42][43] A hallmark of NELL1 activity is the modulation of the pro-inflammatory response in systemic inflammatory diseases and acute tissue injuries. 37,[41][42][43] In contrast to stem cell therapies currently undergoing clinical testing in COVID-19 patients, NELL1 (1) promotes tissue repair without the associated effects of uncontrolled growth and immune system rejection, and (2) is a recombinant protein that does not rely on complex and laborious stem cell resources.…”