Mesenchymal stem cells secretome: a new paradigm for central nervous system regeneration?

Abstract

The low regeneration potential of the central nervous system (CNS) represents a challenge for the development of new therapeutic strategies. Mesenchymal stem cells (MSCs) have been proposed as a possible therapeutic tool for CNS disorders. In addition to their differentiation potential, it is well accepted nowadays that their beneficial actions can also be mediated by their secretome. Indeed, it was already demonstrated, both in vitro and in vivo, that MSCs are able to secrete a broad range of neuroregulatory factors that promote an increase in neurogenesis, inhibition of apoptosis and glial scar formation, immunomodulation, angiogenesis, neuronal and glial cell survival, as well as relevant neuroprotective actions on different pathophysiological contexts. Considering their protective action in lesioned sites, MSCs' secretome might also improve the integration of local progenitor cells in neuroregeneration processes, opening a door for their future use as therapeutical strategies in human clinical trials. Thus, in this review we analyze the current understanding of MSCs secretome as a new paradigm for the treatment of CNS neurodegenerative diseases.

Fig. 1

Mesenchymal stem cell-based therapy for PD. PD is characterized by a progressive neuronal death of dopaminergic neurons in multiple dopaminergic networks, most intensively in the nigrostriatal pathway leading to motor complications (a, b). The transplantation of MSCs has emerged as possible therapeutic tool due to their proliferation and differentiation capacity (c). The ability to release growth and trophic factors seems to be one of the reasons for their contribution to the protection/survival of the preexisting dopaminergic neurons in lesioned areas, leading to functional amelioration and improvement of motor function. (SN substantia nigra)

Fig. 2

Mesenchymal stem cell-based therapy for SCI. SCI leads to immediate neuronal and glial cell death with interruption of ascending and descending pathways, followed by intense inflammatory reaction and glial scar formation (a, b). The transplantation of MSCs has been described to contribute for the recruitment of new neural stem cells, neuronal and glial cells, promoted by cell–cell interaction or by the release of cytokines, and trophic factors (c). The secretion of these cytokines and trophic factors seems to be the main effector of neuroprotective processes and for reduction of the glial scar, modulation of inflammation, and stimulation of the remyelination (adapted from Lindvall and Kokaia [2])

Fig. 3

Mesenchymal stem cell-based therapy for stroke. This pathology is caused by occlusion of a cerebral artery, leading to focal tissue loss with death of different neural cells, including neurons and glial cells as well as endothelial cells (a, b). MSCs transplantation has been shown to have a beneficial role in the reduction of lesion size and in the protection of surviving cells (c). The secretion of growth and trophic factors has been associated with motor and functional recovery, having a key role on neuroprotection and modulation of inflammation

Fig. 4

Mechanisms of action of MSCs in the CNS. a The transdifferentiation capacity of MSCs into neuronal and glial lineages both in vitro and in vivo was described over the years as the probable explanation by their beneficial outcomes after transplantation in the CNS, although this concept remains still unclear. b The trophic action of MSCs has been increasingly accepted nowadays as a new concept to the regeneration of the CNS. The secretion of growth and neurotrophic factors by these cells has been described as an assistant in the nervous tissue regeneration through the activation/modulation of some endogenous processes like the promotion of neurogenesis, angiogenesis, and immunomodulation, contributing in this way to the neuroprotection and regeneration of the CNS