A stably self-renewing adult blood-derived induced neural stem cell exhibiting patternability and epigenetic rejuvenation.
Chao ShengJohannes JungverdorbenHendrik WiethoffQiong LinLea J FlitschDaniela EckertMatthias HebischJulia FischerJaideep KesavanBeatrice WeykopfLinda SchneiderDominik HoltkampHeinz BeckAndreas TillUllrich WüllnerMichael J ZillerWolfgang WagnerMichael PeitzOliver BrüstlePublished in: Nature communications (2018)
Recent reports suggest that induced neurons (iNs), but not induced pluripotent stem cell (iPSC)-derived neurons, largely preserve age-associated traits. Here, we report on the extent of preserved epigenetic and transcriptional aging signatures in directly converted induced neural stem cells (iNSCs). Employing restricted and integration-free expression of SOX2 and c-MYC, we generated a fully functional, bona fide NSC population from adult blood cells that remains highly responsive to regional patterning cues. Upon conversion, low passage iNSCs display a profound loss of age-related DNA methylation signatures, which further erode across extended passaging, thereby approximating the DNA methylation age of isogenic iPSC-derived neural precursors. This epigenetic rejuvenation is accompanied by a lack of age-associated transcriptional signatures and absence of cellular aging hallmarks. We find iNSCs to be competent for modeling pathological protein aggregation and for neurotransplantation, depicting blood-to-NSC conversion as a rapid alternative route for both disease modeling and neuroregeneration.
Keyphrases
- dna methylation
- stem cells
- genome wide
- gene expression
- high glucose
- diabetic rats
- transcription factor
- spinal cord
- drug induced
- poor prognosis
- endothelial cells
- neural stem cells
- emergency department
- autism spectrum disorder
- drug delivery
- cell proliferation
- bone marrow
- long non coding rna
- sensitive detection
- cell fate
- induced pluripotent stem cells