Neural progenitor cells derived from fibroblasts induced by small molecule compounds under hypoxia for treatment of Parkinson’s disease in rats

Neural progenitor cells(NPCs) capable of self-renewal and differentiation into neural cell lineages offer broad prospects for cell therapy for neurodegenerative diseases. However, cell therapy based on NPC transplantation is limited by the inability to acquire sufficient quantities of NPCs. Previous studies have found that a chemical cocktail of valproic acid, CHIR99021, and Repsox(VCR) promotes mouse fibroblasts to differentiate into NPCs under hypoxic conditions. Therefore, we used VCR(0.5 mM valproic acid, 3 μM CHIR99021, and 1 μM Repsox) to induce the reprogramming of rat embryonic fibroblasts into NPCs under a hypoxic condition(5%). These NPCs exhibited typical neurosphere-like structures that can express NPC markers, such as Nestin, SRY-box transcription factor 2, and paired box 6(Pax6), and could also differentiate into multiple types of functional neurons and astrocytes in vitro. They had similar gene expression profiles to those of rat brain-derived neural stem cells. Subsequently, the chemically-induced NPCs(ciNPCs) were stereotactically transplanted into the substantia nigra of 6-hydroxydopamine-lesioned parkinsonian rats. We found that the ciNPCs exhibited long-term survival, migrated long distances, and differentiated into multiple types of functional neurons and glial cells in vivo. Moreover, the parkinsonian behavioral defects of the parkinsonian model rats grafted with ciNPCs showed remarkable functional recovery. These findings suggest that rat fibroblasts can be directly transformed into NPCs using a chemical cocktail of VCR without introducing exogenous factors, which may be an attractive donor material for transplantation therapy for Parkinson’s disease.

Variaiton in the composition of small molecule compounds in the egg yolks of Asian Short-toed Larks between early and late broods

The egg yolks of birds contain most of the maternally derived materials required for embryo development and are an important factor influencing embryo development and offspring viability.Individual variation in egg-laying date frequently occurs in passerines inhabiting highly seasonal environments.Females laying in early and late stages of the breeding season encounter different environment temperatures and food conditions,which can affect the levels of metabolities in their bodies,thereby altering the transmission of these materials to the eggs.We test a hypothesis that yolk small molecule compounds of Asian Short-toed Lark(Alaudala cheleensis)could vary between early(mid-May)and late(mid-June)broods.Using the UHPLC-MS/MS method,683 compounds belonging to 21 compound groups are detected in the yolks.The contents of 18 compounds are significantly different between early and late broods.Ten differential compounds are significantly higher in the early laid eggs,among whichγ-aminobutyric acid,creatine,prostaglandins,palmitoleic acid,linoleic acid,and trans linoleic acid are related to low environment temperature response.The eggs laid in late stage exhibit significantly higher levels of 5-L-glutamyl-L-alanine andγ-glutamate-leucine,1,3-dimethyluric acid and mannose,which may be attributed to females in the late group consuming more insects.We suggest conducting a comprehensive investigation to reveal the yolk small molecule compounds mediated maternal effects on offspring phenotypes under varying ecological conditions.

Small molecule compound induces chromatin de-condensation and facilitates induced pluripotent stern cell generation

The revolutionary induced pturipotent stem celt （iPSC） technoLogy provides a new means for celt replacement therapies and drug screening. Small molecule compounds have been found extremely useful to improve the generation of iPSCs and understand the repro- gramming mechanism. Here we report the identification of a novel chemical, CYT296, which improves OSKM-mediated induction of iPSCs for 〉10 folds and enables efficient reprogramming with only Oct4 in combination with other small molecules. The derived iPSCs are genuinely pluripotent and support the development oftwo ＇All-iPSC＇ mice by tetraploid complementation. CYT296 profoundly impacts heterochromatin formation without affecting celt viability. MEFs treated with CYT296 exhibit de-condensed chromatin structure with markedly reduced loci containing heterochromatin protein 1α （HPIoL） and H3K9me3, which is very similar to the chromatin configuration in embryonic stem cells （ESCs）. Given that an open chromatin structure serves as a hallmark of pLuripotency and has to be acquired to fulfill reprogramming, we propose that CYT296 might facilitate this process by disrupting condensed chromatin, thereby creating a more favorable environment for reprogramming. In agreement of this idea, shRNA targeting HP1α also promotes the generation of iPSCs. Thus current findings not only provide a novel chemical for efficient iPSC induction, but also suggest a new approach to regulate somatic cell reprogramming by targeting chromatin de-condensation with small molecules.