Systemic Dental Pulp Stem Cell Secretome Therapy in a Mouse Model of Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron (MN) disease with no cure. Accumulating evidence indicates ALS involves a complex interaction between central glia and the peripheral immune response and neuromuscular interface. Stem cell secretomes contain various beneficial trophic factors and cytokines, and we recently demonstrated that administration of the secretome of adipose-derived stem cells (ASCs) during early neuromuscular junction (NMJ) denervation in the mutant superoxide dismutase (mSOD1G93A) ALS mouse ameliorated NMJ disruption. In the present study, we hypothesized that administration of dental pulp stem cell secretome in the form of conditioned medium (DPSC-CM) at different stages of disease would promote NMJ innervation, prevent MN loss and extend lifespan. Our findings show that DPSC-CM significantly improved NMJ innervation at postnatal day (PD) 47 compared to vehicle treated mSOD1G93A mice (p < 0.05). During late pre-symptomatic stages (PD70-P91), DPSC-CM significantly increased MN survival (p < 0.01) and NMJ preservation (p < 0.05), while reactive gliosis in the ventral horn remained unaffected. For DPSC-CM treated mSOD1G93A mice beginning at symptom onset, post-onset days of survival as well as overall lifespan was significantly increased compared to vehicle treated mice (p < 0.05). This is the first study to show therapeutic benefits of systemic DPSC secretome in experimental ALS, and establishes a foundation for future research into the treatment effects and mechanistic analyses of DPSC and other stem cell secretome therapies in ALS.

Dental Stem Cell-Derived Secretome/Conditioned Medium: The Future for Regenerative Therapeutic Applications

“…The therapeutic potential of dental pulp MSC-CM systemic administration in a mutant superoxide dismutase mouse model of amyotrophic lateral sclerosis was demonstrated [149]. Dental pulp MSC-CM improved neuromuscular junction innervation and motor neuron survival in treating amyotrophic lateral sclerosis through different trophic factors and cytokines [149].…”

“…The therapeutic potential of dental pulp MSC-CM systemic administration in a mutant superoxide dismutase mouse model of amyotrophic lateral sclerosis was demonstrated [149]. Dental pulp MSC-CM improved neuromuscular junction innervation and motor neuron survival in treating amyotrophic lateral sclerosis through different trophic factors and cytokines [149]. Similarly, dental pulp MSC-CM exhibited neuroprotective, anti-inflammatory, and angiogenic actions when administrated into unilateral hind limb skeletal muscles of a diabetic polyneuropathy rat model [150].…”

Insight into the Role of Dental Pulp Stem Cells in Regenerative Therapy

“…It has been shown that conditioned medium obtained from MSCs has therapeutic effects in several somatic disorders [ 140 , 141 ]. Conditioned medium from DPSCs and SHEDs have also been clarified to have regenerative potential [ 142 , 143 , 144 , 145 ]. Although the main substance contained in conditioned medium and exerting therapeutic effects has not been clarified, exosomes might play an important role in regenerative processes.…”

Human Dental Pulp Stem Cells: recent findings and current research

“…DPSCs are introduced into the field of stem cell therapy to treat neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), due to therapeutic effect of their neurotrophic factors (VEGF, BDNF or NGF) on spinal and motor neurons [40]. Transplantation of cultured DPSCs, containing brain derived neurotrophic factor and nerve growth factor, naturally stimulated the angiogenesis and neurite outgrowth of cultured dorsal root ganglion neurons [41].…”

“…Animal studies on rat facial nerve regeneration prove therapeutic effect of human immature dental pulp stem cells secreting neurotrophic factors that promote functional recovery of the facial nerve and to trigger mobilization of neuronal survival [44]. Cell therapy by Wang et al showed preservation of neuromuscular junction innervation and motor neuron survival by administration (at progressing stages of disease) of containing cytokines and trophic factors DPSCs secretome [40]. Therefore, due to neural crest origin, DPSCs show promise as good alternative to be reprogrammed into stem cells of neural lineages [45].…”