Adult Stem Cell Possess Internal Machinery to Resist Ischemic Injury

Adult stem cells that have been transplantation into a sick patient are often faced with harsh conditions that lead to their untimely death before they can help the patient. Several different strategies have been applied to stem cells to “toughen them up” so that they can resist these conditions. Treating them with particular growth factors have proven effective in some experiments, as has oxygen or glucose deprivation. A recent paper in the journal ANTIOXIDANTS & REDOX SIGNALING by Gang Lu, Muhammad Ashraf, and Khawaja Husnain Haider from the Department of Pathology at the University of Cincinnati, Ohio has shown that treatment of stem cells with insulin-like growth factor-1 (IGF-1) and glucose and oxygen deprivation activate a biochemical pathway that seems to be common to many different types of stem cells that help cell resist ischemic (oxygen-poor) conditions.

This paper examined bone marrow stem cells. When the bone marrow stem cells were deprived of oxygen and glucose for 12 hours, they discovered that a well-known signaling molecule called ERK1/2 was activated. ERK1/2 stands for “extracellular signal-related kinases-1/2. These molecules are “kinases,” which simply means that they are enzymes that attach phosphate groups to other proteins. These phosphate groups change the 3-D structure of proteins can induce them to change they function. ERK1/2 are activated whenever the cell binds particular types of growth factors. Growth factor-binding sets a series of steps in motion that leads to the activation of ERK1/2. ERK1/2 phosphorylates its target, which sets a phosphorylation cascade into motion, and this changes the behavior of the cell.

There are ways to inhibit ERK1/2 activation, and when the University of Ohio team did just that (with a drug called PD98059), the bone marrow stem cells did not activate ERK1/2 when derived of oxygen and glucose and the cells died. This shows that activation of ERK1/2 occurs as a result of oxygen and glucose deprivation, and the activation of ERK1/2 is required for the cells to survive the harsh conditions.

Next, they discovered that ERK1/2 is also activated by treating the cells with IGF-1. Since IGF-1 treatment also helps stem cells adapt to harsh conditions, it is possible that these two treatments use the same internal mechanism to help stem cells adapt to harsh conditions.

What is a downstream target of ERK1/2 that throws the switch that allows cells to adapt the harsh conditions? The researchers received two clues when they discovered that drugs that prevent the release of calcium ion stores into the cell interior also prevent cells from adapting to harsh conditions. This tipped them off that a target of calcium-ion signaling was probably the downstream target of ERK1/2. That target is protein kinase C (PKC).

To shore up their hypothesis, they treated stem cells with a chemical that is known to activate PKC (phorbol esters). These chemicals completely acclimatized the cells to harsh conditions and when the bone marrow stem cells were grown after they had been engineered with a permanently active form of PKC, the stem cells did not require any preconditioning in order to resist harsh conditions.

These data are remarkable and since calcium signaling is a pathway that we know a great deal about and there are lots of chemicals available to manipulate it, it should be possible to precondition a whole host of stem cells to resist harsh conditions before they are ever used. These types of treatments should improve adult stem cell treatments for a variety of conditions.