Abstract
Damage to the nervous system can cause devastating diseases or musculoskeletal dysfunctions and transplantation of progenitor stem cells can be an excellent treatment option in this regard. Preclinical studies demonstrate that untreated stem cells, unlike stem cells activated to differentiate into neuronal lineage, do not survive in the neuronal tissues. Conventional methods of inducing neuronal differentiation of stem cells are complex and expensive. We therefore sought to determine if a simple, one-step, and cost effective method, previously reported to induce neuronal differentiation of embryonic stem cells and induced-pluripotent stem cells, can be applied to adult stem cells. Indeed, dual inhibition of activin/nodal/TGF-β and BMP pathways using SB431542 and dorsomorphin, respectively, induced neuronal differentiation of human adipose derived stem cells (hADSCs) as evidenced by formation of neurite extensions, protein expression of neuron-specific gamma enolase, and mRNA expression of neuron-specific transcription factors Sox1 and Pax6 and matured neuronal marker NF200. This process correlated with enhanced phosphorylation of p38, Erk1/2, PI3K, and Akt1/3. Additionally, in vitro subcutaneous implants of SB431542 and dorsomorphin treated hADSCs displayed significantly higher expression of active-axonal-growth-specific marker GAP43. Our data offers novel insights into cell-based therapies for the nervous system repair.
Highlights
The human nervous system consists of the brain, spinal cord, autonomic nervous system, and peripheral nerves
To induce differentiation into Schwann cell phenotype using conventional method, human adipose derived stem cells (hADSCs) were grown in the nerve induction medium (NIM) in three consecutive steps: (1) hADSCs were treated with 1 mM β-mercaptoethanol in serum-free and ascorbate-free basal medium (BM) for 24 hours, (2) the cells were grown in BM supplemented with 0.28 μg/mL retinoic acid for 3 days, and (3) after retinoic acid treatment for 3 days the cells were transferred to BM supplemented with a mixture of growth factors 10 μM forskolin
To obtain morphological confirmation that inhibition of activin/nodal/TGF-β and BMP pathways induces neuronal differentiation of hADSCs, we compared the morphology of DM or SB or DM + SB treated cells with hADSCs cultured in control BM
Summary
The human nervous system consists of the brain, spinal cord, autonomic nervous system (controlling involuntary functions such as heart rate, digestion, salivation, perspiration, urination, sexual arousal, and breathing), and peripheral nerves. Cajal’s dogma that the neurons in the central nervous system (CNS) cannot regenerate has been refuted, it is recognized that the CNS lacks the ability to regenerate itself for the reestablishment of the correct axonal and dendritic connections [1] Due to this inherent limitation, any damage to the CNS whether through neurodegenerative disease or trauma leads to devastating consequences such as Parkinson’s disease, Alzheimer’s diseases, or traumatic or ischemic brain injury. Nerve injury can result from a nerve laceration or from avulsion of the nerve from its muscular insertion, both of which can result in fibrotic degeneration of the nerve and its motor unit due to loss of nerve signaling [3]. Most patients treated with these techniques have poor muscle
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