Exosomes derived from human placental mesenchymal stem cells enhanced the recovery of spinal cord injury by activating endogenous neurogenesis

Abstract

Background Spinal cord injury (SCI) is a debilitating medical condition that can result in the irreversible loss of sensorimotor function. Current therapies fail to provide an effective recovery being crucial to develop more effective approaches. Mesenchymal stem cell (MSC) exosomes have been shown to be able to facilitate axonal growth and act as mediators to regulate neurogenesis and neuroprotection, holding great therapeutic potential in SCI conditions. This study aimed to assess the potential of human placental MSC (hpMSC)-derived exosomes on the functional recovery and reactivation of endogenous neurogenesis in an experimental animal model of SCI and to explore the possible mechanisms involved. Methods The hpMSC-derived exosomes were extracted and transplanted in an experimental animal model of SCI with complete transection of the thoracic segment. Functional recovery, the expression of neural stem/progenitor cell markers and the occurrence of neurogenesis, was assessed 60 days after the treatment. In vitro, neural stem cells (NSCs) were incubated with the isolated exosomes for 24 h, and the phosphorylation levels of mitogen-activated protein kinase kinase (MEK), extracellular signal-regulated kinases (ERK), and cAMP response element binding (CREB) proteins were assessed by western blot. Results Exosomes were successfully isolated and purified from hpMSCs. Intravenous injections of these purified exosomes significantly improved the locomotor activity and bladder dysfunction of SCI animals. Further study of the exosomes’ therapeutic action revealed that hpMSC-derived exosomes promoted the activation of proliferating endogenous neural stem/progenitor cells as denoted by the significant increase of spinal SOX2+GFAP+, PAX6+Nestin+, and SOX1+KI67+ cells. Moreover, animals treated with exosomes exhibited a significative higher neurogenesis, as indicated by the higher percentage of DCX+MAP 2+ neurons. In vitro, hpMSC-derived exosomes promoted the proliferation of NSCs and the increase of the phosphorylated levels of MEK, ERK, and CREB. Conclusions This study provides evidence that the use of hpMSC-derived exosomes may constitute a promising therapeutic strategy for the treatment of SCI.

MicroRNA-Enriched Exosomes from Different Sources of Mesenchymal Stem Cells Can Differentially Modulate Functions of Immune Cells and Neurogenesis

“…It has been reported that MSCs from WJ and BM release several factors that promote neurogenesis, but WJ-MSCs expressed more genes associated with neurogenesis [ 55 ]. Exosomes from MSCs also promoted neurogenesis in animal models of Alzheimer disease [ 54 ] and traumatic brain injury [ 56 ] and can enhance recovery in the case of spinal cord injury [ 57 ].…”

Human-Induced Neural and Mesenchymal Stem Cell Therapy Combined with a Curcumin Nanoconjugate as a Spinal Cord Injury Treatment

“…Finally, Sun et al demonstrated that the sub-acute co-transplantation of human NSC and MSC enhanced stem cell survival compared to individual treatments, increased the number of myelinated axons, and improved locomotor function [ 52 ]. The use of MSC secretome, alone or in combination with NSC, would provide a successful alternative to cell therapy, since researchers have ascribed paracrine effects to exosomes in the treatment of spinal cord injuries including anti-inflammatory [ 53 ], angiogenic [ 54 ] and regenerative effects [ 55 ], as well as functional recovery [ 56 ].…”

Therapeutic Effect of Exosomes Derived From Stem Cells in Spinal Cord Injury: A Systematic Review Based on Animal Studies

“…Among the included 32 studies, only two studies were controlled studies (29,33), and the remaining 30 studies were randomized controlled studies. The species of animals included SD rats (19-21, 28-37, 39, 40, 42-44, 46, 47, 49-53, 55, 56), Wistar rats (41,54), and C57BL/6 mice (38,45,48); gender included male (28, 30-32, 38-45, 49, 53, 54) and female (19, 20, 29, 33, 34, 36, 37, 46-48, 50-52, 55, 56), two studies did not report the sex of the animals (21,35); the weights of animals were between 150 (41) and 300 g (20,44), the weight of the mouse was between 17 and 22 g ( 48), and seven of the studies did not report the weight of the animals (21,29,30,38,42,45,50); age was between 6 (38,44,45,50,51) and 12 weeks (47, 56), and nine of the studies did not report the age of the animals (19, 21, 35-37, 42, 46, 51, 52); samples size were between 10 (51) and 100 (41); models of SCI included contusion (20, 21, 28-32, 34-53, 56), hemisection (54), and transection (19,33,55); the types of exosomes included the exosomes of bone marrow mesenchymal stem cells of SD rats (BMSCs-Exo) (20, 21, 28, 30, 34-37, 39, 42-44, 47, 49, 52, 53, 56), BMSCs-Exo of Wistar rats (41,54), BMSCs-Exo of human (19,33,…”