Autologous transplants of Adipose-Derived Adult Stromal (ADAS) cells afford dopaminergic neuroprotection in a model of Parkinson's disease

Abstract

Adult adipose contains stromal progenitor cells with neurogenic potential. However, the stability of neuronal phenotypes adopted by Adipose-Derived Adult Stromal (ADAS) cells and whether terminal neuronal differentiation is required for their consideration as alternatives in cell replacement strategies to treat neurological disorders is largely unknown. We investigated whether in vitro neural induction of ADAS cells determined their ability to neuroprotect or restore function in a lesioned dopaminergic pathway. In vitro-expanded naïve or differentiated ADAS cells were autologously transplanted into substantia nigra 1-week after an intrastriatal 6-hydroxydopamine injection. Neurochemical and behavioral measures demonstrated neuroprotective effects of both ADAS grafts against 6-hydroxydopamine-induced dopaminergic neuron death, suggesting that pre-transplantation differentiation of the cells does not determine their ability to survive or neuroprotect in vivo. Therefore, we investigated whether equivalent protection by naïve and neurally-induced ADAS grafts resulted from robust in situ differentiation of both graft types into dopaminergic fates. Immunohistological analyses revealed that ADAS cells did not adopt dopaminergic cell fates in situ, consistent with the limited ability of these cells to undergo terminal differentiation into electrically active neurons in vitro. Moreover, re-exposure of neurally-differentiated ADAS cells to serum-containing medium in vitro confirmed ADAS cell phenotypic instability (plasticity). Lastly, given that gene expression analyses of in vitro-expanded ADAS cells revealed that both naïve and differentiated ADAS cells express potent dopaminergic survival factors, ADAS transplants may have exerted neuroprotective effects by production of trophic factors at the lesion site. ADAS cells may be ideal for ex vivo gene transfer therapies in Parkinson's disease treatment.

Adipose Tissue Derived Stem Cells Secretome: Soluble Factors and Their Roles in Regenerative Medicine

“…Nevertheless this work served as a background for forthcoming papers dealing with this subject. The reports of McCoy et al [61] and Wei et al [59] are good examples of this.…”

1980-2011: Parkinson's Disease and Advance in Stem Cell Research

“…Partial maintenance of neuron survival and function in the SNc within the neurodegenerative environment, following transplantation of SCs could, per se, potentially translate in significant therapeutic outcomes. Substantial neuroprotective effects against dopaminergic depletion have been observed, for example, after transplantations of naïve, undifferentiated SCs such as adult adipose-derived adult stromal cells (McCoy et al, 2008), human NSC (Yasuhara et al, 2006) or human MSC (Blandini et al, 2010) in 6-OHDA lesioned rats.…”

Advances in the Combined Use of Adult Cell Therapy and Scaffolds for Brain Tissue Engineering

“…Naïve hMSCs or a subpopulation of hMSC pre-treated with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) also led to an efficient recovery after partial lesions, suggesting a paracrine restorative effect by MSCs. Indeed, hMSCs, that migrate toward lesions (Hellmann et al, 2006;Sadan et al, 2009;Delcroix et al, 2011) may induce a protective or restorative effect on the remaining neurons within the host brain, due to the secretion of a large panel of neurotrophic factors, including brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), which may also enhance endogenous neurogenesis (Levy et al, 2008;McCoy et al, 2008;Bahat-Stroomza et al, 2009;Sadan et al, 2009). MSCs may also modulate the host response to the lesion (Kim et al, 2008) and probably ultimately replace functional cells within the host brain as a few MSCs with neuronal-like morphology and markers were observed in a total lesion model (Levy et al, 2008).…”