Chemical and Physical Approaches to Extend the Replicative and Differentiation Potential of Stem Cells

Abstract

Cell therapies using mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) are increasing in regenerative medicine, with applications to a growing number of aging-associated dysfunctions and degenerations. For successful therapies, a certain mass of cells is needed, requiring extensive ex vivo expansion of the cells. However, the proliferation of both MSCs and EPCs is limited as a result of telomere shortening-induced senescence. As cells approach senescence, their proliferation slows down and differentiation potential decreases. Therefore, ways to delay senescence and extend the replicative lifespan these cells are needed. Certain proteins and pathways play key roles in determining the replicative lifespan by regulating ROS generation, damage accumulation, or telomere shortening. And, their agonists and gene activators exert positive effects on lifespan. In many of the treatments, importantly, the lifespan is extended with the retention of differentiation potential. Furthermore, certain culture conditions, including the use of specific atmospheric conditions and culture substrates, exert positive effects on not only the proliferation rate, but also the extent of proliferation and differentiation potential as well as lineage determination. These strategies and known underlying mechanisms are introduced in this review, with an evaluation of their pros and cons in order to facilitate safe and effective MSC expansion ex vivo.

Enhancement of Replication and Differentiation Potential of Human Bone Marrow Stem Cells by Nicotinamide Treatment

“…Stem cells are generally characterized as able to multiply for long periods without changes in their pluripotency. However, MSCs lose functionality during in vitro cultivation and during aging ( 3 ). Like other normal human cells such as fibroblasts, MSCs are subject to limitations in doubling capacity (or replicative life span) and enter a stage called replicative senescence, which is mainly attributed to telomere shortening ( 4 ).…”

Prolonged Growth Hormone/Insulin/Insulin-like Growth Factor Nutrient Response Signaling Pathway as a Silent Killer of Stem Cells and a Culprit in Aging

“…However, with a few exceptions [54, 55] the evidence that antioxidants or other means of prevention of oxidative DNA damage can extend the lifespan or reduce the symptoms of aging, is scarce [56]. On other hand, as cited above, the evidence that the constitutive signaling along the axis GH/INS/IGF–mTOR–S6 K1 (“TOR mechanism”) is the driving force that accelerates aging is compelling.…”

Stem Cells and Regenerative Medicine

“…There are various internal and external factors that trigger the differentiation of stem cells. [40] There are genes in stem cell DNA that can create various tissues. One of the factors that affect division is telomer length.…”

“…One of the factors that affect division is telomer length. [40] External factors that contribute stem cell differentiation are: chemical secreted by neighboring cells, physical connections with neighboring cells and molecules in the microcirculation. [40]…”