Co-Transplantation of Adipose Tissue-Derived Stromal Cells and Olfactory Ensheathing Cells for Spinal Cord Injury Repair

Abstract

Patients suffering from spinal cord injury (SCI) still have a dismal prognosis. Despite all the efforts developed in this area, currently there are no effective treatments. Therefore, cell therapies have been proposed as a viable alternative to the current treatments used. Adipose tissue-derived stromal cells (ASCs) and olfactory ensheathing cells (OECs) have been used with promising results in different models of SCI, namely due to the regenerative properties of the secretome of the first, and the guidance capability of the second. Using an in vitro model of axonal growth, the dorsal root ganglia explants, we demonstrated that OECs induce neurite outgrowth mainly through cell-cell interactions, while ASCs' effects are strongly mediated by the release of paracrine factors. A proteomic analysis of ASCs' secretome revealed the presence of proteins involved in VEGF, PI3K, and Cadherin signaling pathways, which may be responsible for the effects observed. Then, the cotransplantation of ASCs and OECs showed to improve motor deficits of SCI-rats. Particular parameters of movement such as stepping, coordination, and toe clearance were improved in rats that received the transplant of cells, in comparison to nontreated rats. A histological analysis of the spinal cord tissues revealed that transplantation of ASCs and OECs had a major effect on the reduction of inflammatory cells close the lesion site. A slight reduction of astrogliosis was also evident. Overall, the results obtained with the present work indicate that the cotransplantation of ASCs and OECs brings important functional benefits to the injured spinal cord. Stem Cells 2018;36:696-708.

Influence of passage number on the impact of the secretome of adipose tissue stem cells on neural survival, neurodifferentiation and axonal growth

“…Moreover, it was also shown that ASCs secretome has the ability to induce neuronal differentiation of human neural progenitor cells [59]. Recently, it has been shown that exposure to ASCs secretome promotes axonal growth [29,59]. In the present study we have observed that these effects are not dependent on cell passaging.…”

Cell Secretome: Basic Insights and Therapeutic Opportunities for CNS Disorders

“…Although the mechanism of action remains to be completely understood. Different studies point to the secreted factors and vesicles-their secretome-as agents for the regenerative effect rather than cellular differentiation [14].…”

“…Candidate novel therapies have emerged in the CNS regeneration context, such as molecular therapies [11,12], biomaterials [13], and cellular transplantation [14][15][16]. The last one, cell-based therapies, have brought a particular interest to the CNS regeneration field and have been proposed over the last decades as a possible route to repair damaged circuitries within the CNS.…”

“…Currently, a growing body of evidence points to the importance of the paracrine signaling as a mechanism to support recovery by the transplanted cells. For instance, it has been demonstrated that the beneficial effects observed upon mesenchymal stem cell (MSC) grafts on the injured CNS were mainly due to secreted factors rather than cellular engraftment, in models of spinal cord injury [14] and Parkinson's disease [17], as reviewed elsewhere [18][19][20]. This new paradigm regarding the paracrine action instead of cellular replacement or cell-cell interrelation has originated a new possible therapeutic opportunity, using the cellular secretome to tackle diverse pathologies.…”

Combination of a Gellan Gum-Based Hydrogel With Cell Therapy for the Treatment of Cervical Spinal Cord Injury

“…This approach is based on the combination of adipose tissue-derived stem/stromal cells (ASCs) and olfactory ensheathing cells (OECs), together with a modified Gellan Gum (GG)-based hydrogel, which can be used both as a matrix for neural regrowth, and/or as a vehicle for cellular transplantation. ASCs and OECs represent two distinct cellular populations with complementary effects, as already demonstrated by our group (Silva et al, 2013a;Gomes et al, 2016Gomes et al, , 2018. On one hand, OECs offer physical support and guidance for neurite outgrowth and elongation, mainly through direct cell-cell contact (Ramon-Cueto et al, 2000;Gomes et al, 2018).…”