Improved survival of young donor age dopamine grafts in a rat model of Parkinson’s disease

Meningeal cells influence midbrain development and the engraftment of dopamine progenitors in Parkinsonian mice

“…Here we describe the impact of meningeal cells on graft integration and, using in vitro approaches, demonstrate the mechanisms by which these cells promote differentiation and axonal growth and guidance, including the involvement of SDF1/CXCR4 signaling. Previous studies have focused on the impact of donor age on graft outcomes, demonstrating that the transplantation of younger donor tissue than conventionally used results in larger grafts as a consequence of increased survival and progenitor proliferation at the time of grafting (Bye et al, 2012;Torres et al, 2007). However within these studies little mention has been made of the meninges that, at this young age, remain tightly attached to the underlying brain.…”

“…While previous studies by us, and others have identified young (E10) VM donor tissue as superior to older (E12) for promoting graft size and innervation, due to the increased survival and proliferation of progenitors post-implantation (Bye et al, 2012;Freeman et al, 1995;Gates et al, 2006;Kauhausen et al, 2013;Torres et al, 2007), no attention has been made to the potential contribution of the overlying meninges that may impact on younger tissue preparations. We therefore examined the effect of meningeal cell co-grafting on ventral midbrain graft survival and integration in 6OHDA lesioned mice.…”

“…Human fetal ventral mesencephalic (VM) dopaminergic progenitors, ectopically transplanted into the striatum of Parkinsonian patients, have been shown to structurally and functionally integrate and alleviate symptoms for more than a decade (Winkler et al, 2005). In an effort to improve the survival and integration of these new neurons into the denervated striatum, studies by us and others, have demonstrated that the use of younger donor tissue results in superior outcomes (Bye et al, 2012;Freeman et al, 1995;Gates et al, 2006;Kauhausen et al, 2013;Torres et al, 2007).…”

“…However the transplantation of younger VM tissue (E10) has been shown to result in grafts containing more DA neurons, a greater proportion of A9 DA neurons (the DA subpopulation responsible for restoring motor function following transplantation (Grealish et al, 2010;Kuan et al, 2007)), increased striatal reinnervation and elevated dopamine levels (Bye et al, 2012;Torres et al, 2007). In part, these improved findings were attributed to enhanced survival and increased numbers of dividing dopaminergic neuroblasts at the time of transplantation in younger versus older donor grafts (Bye et al, 2012;Torres et al, 2007), as well as the observation that A9 DA neurons precede the birth of other midbrain DA neurons during development, and are thereby enriched for in younger tissue (Blaess et al, 2011;Bye et al, 2012;Hayes et al, 2011;Joksimovic et al, 2009). However it remains to be determined whether other variables may have influenced these improved outcomes.…”

Transplantation in the nonhuman primate MPTP model of Parkinson's disease: update and perspectives

“…For example, VM tissue isolated from early stage fetuses showed a higher survival rate than that of older stage fetuses (Sladek Jr. et al, 1993b;Collier et al, 2002), as was previously shown in rodents (Fricker et al, 1997;Torres et al, 2007;Torres et al, 2008). Similarly, early DA progenitors derived from primate PSCs (D21-D28 neurospheres) produced larger grafts (Kikuchi et al, 2011) and showed a higher survival rate (Takagi et al, 2005;Wang et al, 2015) than did late DA neurons (D42 neurospheres; Sanchez-Pernaute et al, 2005;Takagi et al, 2005;Kikuchi et al, 2011;Doi et al, 2012;Emborg et al, 2013a).…”