Improving and accelerating the differentiation and functional maturation of human stem cell‐derived neurons: role of extracellular calcium and GABA

Abstract

Neurons differentiated from pluripotent stem cells using established neural culture conditions often exhibit functional deficits. Recently, we have developed enhanced media which both synchronize the neurogenesis of pluripotent stem cell-derived neural progenitors and accelerate their functional maturation; together these media are termed SynaptoJuice. This pair of media are pro-synaptogenic and generate authentic, mature synaptic networks of connected forebrain neurons from a variety of induced pluripotent and embryonic stem cell lines. Such enhanced rate and extent of synchronized maturation of pluripotent stem cell-derived neural progenitor cells generates neurons which are characterized by a relatively hyperpolarized resting membrane potential, higher spontaneous and induced action potential activity, enhanced synaptic activity, more complete development of a mature inhibitory GABA receptor phenotype and faster production of electrical network activity when compared to standard differentiation media. This entire process - from pre-patterned neural progenitor to active neuron - takes 3 weeks or less, making it an ideal platform for drug discovery and disease modelling in the fields of human neurodegenerative and neuropsychiatric disorders, such as Huntington's disease, Parkinson's disease, Alzheimer's disease and Schizophrenia.

Kv7 channels are upregulated during striatal neuron development and promote maturation of human iPSC-derived neurons

“…Therefore, using the hiPSCs pre-patterned by an established technique of dual SMAD and Wnt inhibition [20, 26, 37], a detailed determination of both the expression of KCNQ mRNA and Kv7 subunits in these developing striatal-like neurons was performed using the control hiPSC line, CS83iCTR33Qn1 (CTR33Qn1). KCNQ2 and KCNQ5 mRNA both increased early (23 dpp), whilst KCNQ3 and KCNQ4 showed no significant differences during the differentiation protocol.…”

Role of Calcium Bio-Minerals in Regenerative Medicine and Tissue Engineering

“…However, to maintain cytosolic calcium concentrations and generate spontaneous calcium oscillations in mesenchymal stem cells electric pulses are used [50]. For improving and accelerating the differentiation and functional maturation of human stem cellderived neurons extracellular calcium and GABA play important role [51]. Monolithic calcium phosphate/poly(lactic acid) composite versus calcium phosphate-coated poly(lactic acid) are also used to support osteogenic differentiation of human mesenchymal stromal cells [52].…”

Human Models Are Needed for Studying Human Neurodevelopmental Disorders

“…This major limitation is being addressed in culture through the use of three-dimensional cultures, mixed neuron and astrocyte cultures, and the development of new media. [350][351][352] Chimeras, in which hPSC-derived neurons are implanted into the mouse central nervous system, address the challenge by providing an environment that stimulates the maturation of human neurons.…”