Cellular therapies have started an important new therapeutic direction in autistic spectrum disorder (ASD), and the ample diversity of ASD pathophysiology and the different types of cell therapies prompt an equally ample effort to employ clinical studies for studying the ASD causes and cell therapies. Stem cells have yielded so far mixed results in clinical trials, and at patient level the results varied from impressive to no improvement. In this context we have administered autologous cord blood (ACB) and a non-placebo, material intervention represented by an individualized combination of supplements (ICS) to ASD children.

To compare the efficacy of ACB vs ICS and find markers correlated with the child's progress in order to better predict ACB efficacy.

CORDUS clinical study is a crossover study in which both oral ICS and intravenous ACB were sequentially administered to 56 children; ACB was infused as an inpatient procedure. Treatment efficacy was evaluated pre-treatment and post-treatment at 6 months by an independent psychotherapist with Autism Treatment Evaluation Checklist, Quantitative Checklist for Autism in Toddlers and a 16-item comparative table score, after interviewing the children’s parents and therapists. Before and after each intervention participants had a set of blood tests including inflammatory, metabolic and oxidative markers, and the neuronal specific enolase.

No serious adverse reactions were noted during and after cord blood or supplement administration. ACB improved evaluation scores in 78% of children with age 3–7-years (n = 28), but was much less effective in kids older than 8 years or with body weight of more than 35 kg (n = 28; only 11% of children improved scores). ICS yielded better results than ACB in 5 cases out of 28, while in 23 kids ACB brought more improvement than ICS (P < 0.05); high initial levels of inflammation and ferritin were associated with no improvement. Ample individual differences were noted in children's progress, and statistically significant improvements were seen after ACB on areas such as verbalization and social interaction, but not on irritability or aggressive behavior.

ACB has superior efficacy to ICS in ASD; high inflammation, ferritin, age and body weight predict less improvement; more clinical studies are needed for studying ACB efficacy in ASD.

• Autistic spectrum disorder
• Cord blood
• Stem cells
• Neuroinflammation
• Autologous stem cell treatment
• Neuronal specific enolase

• cell cryopreservation
• cell therapy
• dimethylsulfoxide free
• human T lymphocytes
• ice seeding
• trehalose

• Humans
• Ice
• Trehalose/pharmacology
• T-Lymphocytes
• Cryoprotective Agents/pharmacology
• Cryopreservation/methods
• Dimethyl Sulfoxide/pharmacology
• Cell Survival

• Differentiation
• Human Embryonic Stem Cells (ESCs)
• Induced Pluripotent Stem Cells (iPSCs)
• Neural Progenitor Cells (NPCs)
• Neurons
• Oligodendrocyte Progenitor Cells (OPCs)
• Oligodendrocytes (OLs)

• Humans
• Cells, Cultured
• Cell Differentiation
• Induced Pluripotent Stem Cells
• Oligodendroglia
• Embryonic Stem Cells

• DMSO-free
• biobanking
• biotherapeutics
• cryopreservation
• cryoprotectants
• dimethyl sulfoxide

• Dimethyl Sulfoxide
• Cryopreservation/methods
• Cell Survival

The endoderm, differentiated from human induced pluripotent stem cells (iPSCs), can differentiate into the small intestine and liver, which are vital for drug absorption and metabolism. The development of human iPSC-derived enterocytes (HiEnts) and hepatocytes (HiHeps) has been reported. However, pharmacokinetic function-deficiency of these cells remains to be elucidated. Here, we aimed to develop an efficient differentiation method to induce endoderm formation from human iPSCs. Cells treated with activin A for 168 h expressed higher levels of endodermal genes than those treated for 72 h. Using activin A (days 0–7), CHIR99021 and PI−103 (days 0–2), and FGF2 (days 3–7), the hiPSC-derived endoderm (HiEnd) showed 97.97% CD−117 and CD−184 double-positive cells. Moreover, HiEnts derived from the human iPSC line Windy had similar or higher expression of small intestine-specific genes than adult human small intestine. Activities of the drug transporter P-glycoprotein and drug-metabolizing enzyme cytochrome P450 (CYP) 3A4/5 were confirmed. Additionally, Windy-derived HiHeps expressed higher levels of hepatocyte- and pharmacokinetics-related genes and proteins and showed higher CYP3A4/5 activity than those derived through the conventional differentiation method. Thus, using this novel method, the differentiated HiEnts and HiHeps with pharmacokinetic functions could be used for drug development.

• differentiation
• drug development
• endoderm
• enterocyte
• hepatocyte
• human induced pluripotent stem cell
• pharmacokinetics study

Understanding the molecular properties of the cell cycle of human pluripotent stem cells (hPSCs) is critical for effectively promoting differentiation. Here, we use the Fluorescence Ubiquitin Cell Cycle Indicator system adapted into hPSCs and perform RNA sequencing on cell cycle sorted hPSCs primed and unprimed for differentiation. Gene expression patterns of signaling factors and developmental regulators change in a cell cycle‐specific manner in cells primed for differentiation without altering genes associated with pluripotency. Furthermore, we identify an important role for PI3K signaling in regulating the early transitory states of hPSCs toward differentiation. stem cells2019;37:1151–1157