induced Pluripotent Stem cells from a 69 year old human: the hidden story?

The successful reprogramming (dedifferentiation) of differentiated human somatic cells into a pluripotent, embryonic stem cell-like state called induced pluripotent stem cells (iPS) using just 4 (and recently 3) introduced transcription factors is the biggest news of current stem cell biology. In the paper published in Cell by the Yamanaka group (Takahashi et al.) the iPS clones derived from the facial dermis of a 36-year-old Caucasian female were highlighted. Out of 50 000 retrovirally transduced fibroblasts 10 hES cell-like colonies were observed. But what I found really thought provoking (and poorly discussed in the blogosphere) is that with the same approach iPS cells were generated from the synovial tissue of a 69-year-old Caucasian male. Interestingly out of 50 000 modified cells 17 hES cell-like colonies were found. This finding could easily be relevant from a stem cell aging point of view.

During ageing there is an overall decline in tissue regenerative potential, but it is not clear whether it is due to the intrinsic exhaustion of the adult tissue stem cells or the diminished functionality of the stem cell niche or a change in the systemic milieu. Answers could be different – tissue by tissue.

But if a terminally differentiated connective tissue cell, like the synoviocyte above could be completely reprogrammed from a 69 year old, otherwise health individual into a pluripotent state….well it could it be interpreted as an argument against the cell-intrinsic genetic aging program in adult and aged connective tissues with some cautions.

Caution 1: What if the source of the iPS cells were not really terminally differentiated, but undifferentiated stem or progenitor cells coexisting in fibroblast culture. This problem has been discussed in the paper and forms the Achilles’ heel of it.

Caution 2: The reprogrammed iPS cells from an aged person are behaving the same way as the iPS cells from a younger person with no additional cellular aging characteristics.

As the critical tail of almost every peer-reviewed paper used to say: Further study is needed.

Here is the paragraph on the synoviocytes and the tables and figures are in the supplemental data.

Generation of iPS Cells from Other Human Somatic Cells

In addition to Human Dermal Fibroblast, we used primary human fibroblast-like synoviocytes (HFLS) from synovial tissue of 69-year-old Caucasian male and BJ cells, a cell line established from neonate fibroblasts. From HFLS (5 x 10⁴ cells per 100 mm dish), we obtained more than 600 hundred granulated colonies and 17 hES cell-like colonies. We picked six colonies, of which only two were expandable as iPS cells. Dishes seeded with 5 x 10⁵ HFLS were covered with granulated cells, and no hES cell-like colonies were distinguishable. In contrast, we obtained 7 to 8 and 100 hES cell-like colonies from 5 x 10⁴ and 5 x 10⁵ BJ cells, respectively, with only a few granulated colonies. We picked six hES cell-like colonies and generated iPS cells from five colonies. Human iPS cells derived from HFLS and BJ expressed hES cell-marker genes at levels similar to or higher than those in hES cells. They differentiated into all three germ layers through EBs. STR analyses confirmed that iPS-HFLS cells and iPS-BJ cells were derived from HFLS and BJ fibroblasts, respectively.