Stem cells in amyotrophic lateral sclerosis: Ready for prime time?

Amyotrophic lateral sclerosis (ALS) is the neurodegenerative disease caused by systematic unraveling of the motor network, resulting in progressive loss of upper and lower motor neurons, leading to muscle wasting and weakness, culminating in ventilatory failure and death.¹ There are no treatments that prevent the inexorable course. Stem cells have been promoted as potential therapy for ALS based on their ability to self-renew and differentiate into multiple cell types with the ultimate goal of repairing or replacing injured cells. However, replacing injured cells does not have a high likelihood of successfully treating ALS. Even if stem cells differentiated into motor neurons, it would be difficult to imagine the new motor neurons reproducing the extensive connections lost among cortical neurons, or between specific cortical neurons and their spinal counterparts, or among spinal neurons, or between spinal neurons and their target muscles. Moreover, new motor neurons, if integrated into a diseased network, might be subject to the same pathologic processes that brought about the demise of the original motor neurons. A more attainable goal for stem cells in ALS is that they help extend the lives of spinal motor neurons. The presumptive rationale for transplanting neural progenitor cells (NPCs) in patients with ALS is based on the in vitro demonstration that such cells secrete protective growth factors and, in vivo, can differentiate into neurons and glia that can repair injured cells.² Transplantation of NPCs derived from a single 8-week human fetal spinal cord extended lifespan by 17 days when injected into the spinal cords of G93A SOD rats, a common model of ALS. In these studies, the grafts underwent extensive neuronal and to a lesser extent astrocytic differentiation, presumably mediated by graft intrinsic factors and the host microenvironment.^3,4