4.5 Article

Age-dependent neuroectodermal differentiation capacity of human mesenchymal stromal cells: limitations for autologous cell replacement strategies

期刊

CYTOTHERAPY
卷 12, 期 1, 页码 17-30

出版社

ELSEVIER SCI LTD
DOI: 10.3109/14653240903313941

关键词

mesodermal stromal cells; multipotent differentiation; neural differentiation; telomere length; transdifferentiation

资金

  1. BMBF [AZ 0312126]
  2. BMBF
  3. Dresden Medical Faculty Research Program MeDDrive
  4. Deutsche Forschungsgemeinschaft (DFG)
  5. Collaborative Research Centre 655 Dresden [SFB655-A6]
  6. Landesstiftung Baden-Wurttemberg [AZ 37610]

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Background aims. Human adult bone marrow (BM)-derived mesenchymal stromal cells (hMSC) are reported to break germ layer commitment and differentiate into cells expressing neuroectodermal properties. Although it is of pivotal interest for cell replacement therapies for neurologic disorders, no data exist on the influence of the donor's age on this multipotent differentiation behavior. Methods. We evaluated various epigenetic neuroectodermal conversion protocols in adult hMSC derived from older donors (>45 versus 18-35 years of age) using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and immunocytochemistry. The protocols included single- and multi-step conversion-differentiation protocols combined with co-culture techniques. Furthermore, the age dependency of mesodermal differentiation potential and cell senescence were investigated. Results. The neuroectodermal differentiation potential of hMSC derived from old donors was completely lost, with no cells showing mature neuroectodermal phenotypes using single- and multi-step conversion-differentiation protocols and no improvement of neurogenesis by various co-culture conditions. Comparison of young versus old donor-derived hMSC showed fewer cells expressing early neuroectodermal marker proteins in the latter samples. qRT-PCR showed reduced expression of the proliferation marker K167 and the neuroectodermal gene NES (nestin) in old donor-derived cells compared with young donor hMSC. Telomere length analysis showed no general cell aging. Conclusions. Our data provide evidence that only young donor-derived hMSC can be epigenetically differentiated in vitro into neuroectodermal cells, pointing towards senescence of multipotentiality of old donor-derived hMSC. There is thus an urgent need to develop better protocols for successful neuroectodermal differentiation of hMSC from old individuals as a prerequisite for autologous cell replacement strategies for neurologic diseases in elderly patients.

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