The interaction of stem cells and vascularity in peripheral nerve regeneration

Abstract

The degree of nerve regeneration after peripheral nerve injury can be altered by the microenvironment at the site of injury. Stem cells and vascularity are postulated to be a part of a complex pathway that enhances peripheral nerve regeneration; however, their interaction remains unexplored. This review aims to summarize current knowledge on this interaction, including various mechanisms through which trophic factors are promoted by stem cells and angiogenesis. Angiogenesis after nerve injury is stimulated by hypoxia, mediated by vascular endothelial growth factor, resulting in the growth of pre-existing vessels into new areas. Modulation of distinct signaling pathways in stem cells can promote angiogenesis by the secretion of various angiogenic factors. Simultaneously, the importance of stem cells in peripheral nerve regeneration relies on their ability to promote myelin formation and their capacity to be influenced by the microenvironment to differentiate into Schwann-like cells. Stem cells can be acquired through various sources that correlate to their differentiation potential, including embryonic stem cells, neural stem cells, and mesenchymal stem cells. Each source of stem cells serves its particular differentiation potential and properties associated with the promotion of revascularization and nerve regeneration. Exosomes are a subtype of extracellular vesicles released from cell types and play an important role in cell-to-cell communication. Exosomes hold promise for future transplantation applications, as these vesicles contain fewer membrane-bound proteins, resulting in lower immunogenicity. This review presents pre-clinical and clinical studies that focus on selecting the ideal type of stem cell and optimizing stem cell delivery methods for potential translation to clinical practice. Future studies integrating stem cell-based therapies with the promotion of angiogenesis may elucidate the synergistic pathways and ultimately enhance nerve regeneration.

Keywords: Schwann cells; angiogenesis; exosomes; nerve graft; nerve regeneration; peripheral nerve injury; revascularization; stem cell delivery; stem cells; vascularity.

Figure 1

Schematic drawing of interaction between stem cells, vascularity, and nerve regeneration. After a nerve injury, paracrine cues are provided to stem cells to produce trophic and angiogenic factors that enhance nerve regeneration and angiogenesis, respectively. Blood supply mobilizes stem cells and delivers nutrients and trophic factors to the site of injury to improve nerve regeneration. Blood supply is not only important for the survivability of stem cells but also precedes nerve regeneration after nerve trauma. Copyrighted and used with permission from the Mayo Foundation for Medical Education and Research; all rights reserved.

Figure 2

Schematic overview of different sources of stem cells. Embryonic stem cells are obtained from the inner cell mass of the blastocyst and therefore require destruction of the embryo. Nerve stem cells are harvested from the subventricular layer of the lateral ventricle and the subgranular layer of the hippocampus. Bone marrow-derived stem cells are harvested from the marrow cavity of long bones. Adipose-derived stem cells are derived from subcutaneous fat and are abundantly available following commonly performed procedures such as liposuction. Skin derived precursors are harvested from the dermis and represent a related population of cells harvested from hair follicles. Fetal tissue provides populations of cells from amniotic membrane, amniotic fluid, umbilical cord blood, umbilical cord tissue, and Wharton’s jelly. Dental pulp stem cells can be harvested from deciduous teeth. Copyrighted and used with permission of the World Journal of Stem Cells; all rights reserved. Reprinted with permission from Fairbairn et al. (2015).