Is there a place for human fetal-derived stem cells for cell replacement therapy in Huntington's disease?

Abstract

Huntington's disease (HD) is a neurodegenerative disease that offers an excellent paradigm for cell replacement therapy because of the associated relatively focal cell loss in the striatum. The predominant cells lost in this condition are striatal medium spiny neurons (MSNs). Transplantation of developing MSNs taken from the fetal brain has provided proof of concept that donor MSNs can survive, integrate and bring about a degree of functional recovery in both pre-clinical studies and in a limited number of clinical trials. The scarcity of human fetal tissue, and the logistics of coordinating collection and dissection of tissue with neurosurgical procedures makes the use of fetal tissue for this purpose both complex and limiting. Alternative donor cell sources which are expandable in culture prior to transplantation are currently being sought. Two potential donor cell sources which have received most attention recently are embryonic stem (ES) cells and adult induced pluripotent stem (iPS) cells, both of which can be directed to MSN-like fates, although achieving a genuine MSN fate has proven to be difficult. All potential donor sources have challenges in terms of their clinical application for regenerative medicine, and thus it is important to continue exploring a wide variety of expandable cells. In this review we discuss two less well-reported potential donor cell sources; embryonic germ (EG) cells and fetal neural precursors (FNPs), both are which are fetal-derived and have some properties that could make them useful for regenerative medicine applications.

Protein Misfolding and ER Stress in Huntington's Disease

“…A main set-back of gene therapy approaches is attaining efficient delivery, but there is huge progress in this direction in recent years. Therapy involving fetal cell transplantation has also been attempted (Bachoud-Lévi et al, 2006; Mazzocchi-Jones et al, 2009; Schackel et al, 2013; Precious et al, 2017). The other approach focuses on blocking the cellular toxicity of mHtt.…”

Transplantation in HD: Are We Transplanting the Right Cells?

“…Further to this, we have previously compared survival and axonal outgrowth of transplants of human primary foetal striatal tissue with short-term expanded (10 days) striatal FNPs, where we found richer cellular outgrowth from the FNP-derived grafts [58]. Recently, we have reported that striatal-derived FNPs expanded for short periods in culture prior to transplantation yield the same number of DARPP-32-positive neurons in grafts as those derived from primary foetal WGE [59]. Furthermore, we provided evidence to suggest that short-term expanded (2 and 9 days) striatal FNPs can bring about a degree of functional recovery, specifically on the corridor task (testing bias towards the ipsilateral side and neglect of the side contralateral to the lesion and transplant), following transplantation into an HD rat model [59].…”

“…Recently, we have reported that striatal-derived FNPs expanded for short periods in culture prior to transplantation yield the same number of DARPP-32-positive neurons in grafts as those derived from primary foetal WGE [59]. Furthermore, we provided evidence to suggest that short-term expanded (2 and 9 days) striatal FNPs can bring about a degree of functional recovery, specifically on the corridor task (testing bias towards the ipsilateral side and neglect of the side contralateral to the lesion and transplant), following transplantation into an HD rat model [59]. Collectively, this indicates that FNPs, as a potential donor cell source for application in clinical transplantation, should not be overlooked, but should be further investigated to establish their true potential.…”

Is the Immunological Response a Bottleneck for Cell Therapy in Neurodegenerative Diseases?

“…WGE is the area of the fetal brain which eventually becomes the adult striatum and where the MSNs develop ( Deacon et al, 1994 ; Olsson et al, 1995 , 1998 ; Marín et al, 2000 ; Evans et al, 2012 ; Straccia et al, 2016 ). Hence, cells from this area are considered the “gold standard” for cell replacement in HD as the donor cells have the capacity to differentiate into the target cell type ( Precious et al, 2017 ). It is important to bear in mind that optimal grafts are those derived from fetal WGE collected during the peak period of MSN neurogenesis (around 8-10 weeks of gestation in humans) ( Dunnett and Rosser, 2011 ), whose transplantation has been shown to reduce or delay motor and cognitive deficits in animal studies including rats and non-human primates ( McLeod et al, 2013 ; Schackel et al, 2013 ; Paganini et al, 2014 ; Yhnell et al, 2016 ).…”