Adrenomedullin as a Growth and Cell Fate Regulatory Factor for Adult Neural Stem Cells

Abstract

The use of stem cells as a strategy for tissue repair and regeneration is one of the biomedical research areas that has attracted more interest in the past few years. Despite the classic belief that the central nervous system (CNS) was immutable, now it is well known that cell turnover occurs in the mature CNS. Postnatal neurogenesis is subjected to tight regulation by many growth factors, cell signals, and transcription factors. An emerging molecule involved in this process is adrenomedullin (AM). AM, a 52-amino acid peptide which exerts a plethora of physiological functions, acts as a growth and cell fate regulatory factor for adult neural stem and progenitor cells. AM regulates the proliferation rate and the differentiation into neurons, astrocytes, and oligodendrocytes of stem/progenitor cells, probably through the PI3K/Akt pathway. The active peptides derived from the AM gene are able to regulate the cytoskeleton dynamics, which is extremely important for mature neural cell morphogenesis. In addition, a defective cytoskeleton may impair cell cycle and migration, so AM may contribute to neural stem cell growth regulation by allowing cells to pass through mitosis. Regulation of AM levels may contribute to program stem cells for their use in medical therapies.

Adrenomedullin regulates intestinal physiology and pathophysiology

“…Pio et al [163] demonstrated that AM in milk has a growth-promoting activity on an intestinal cell line (Int-407) because an anti-AM antibody partially blocks the milk-induced growth. This is in line with several studies that have proven that AM acts as an autocrine/paracrine growth factor in other cell types [58,[164][165][166].…”

Adrenomedullin promotes differentiation of oligodendrocyte precursor cells into myelin-basic-protein expressing oligodendrocytes under pathological conditions in vitro

“…AM exerts various actions on the vasculature, such as vasodilation, angiogenesis, and regulation of blood brain barrier. Similarly, AM acts as a neurotransmitter, neuromodulator, or neurohormone [18]. In addition, AM can be considered as a therapeutic target for CNS diseases since several animal studies have demonstrated that AM reduces neuronal injuries [32–35].…”

“…AM has diverse biological actions, including cell proliferation and differentiation in a paracrine and autocrine manner [17–20]. AM also have important roles for cellular function of immature cells, such as endothelial progenitor cell (EPC), mesenchymal stem cell, hematopoietic stem cell, adrenocortical stem cell, and neural stem/progenitor cell (NSPC) [18, 21, 22]. Recently, it has been reported that AM may also regulate white matter function in the brain.…”

Caffeoylquinic acid enhances proliferation of oligodendrocyte precursor cells

“…Adrenomedullin receptors are widely distributed in the brain and AM is reported to act as a neurohormone and neurotransmitter [ 14 ]. Literature has also suggested that neuronal injury can be protected by activating the AM receptor, and thereby effectively aiding in the management of certain CNS disorders [ 15 , 16 ].…”