Personalized Medicine Considers Which Would-Be Stem Cells to Cultivate, and When

February 26, 2016

A human donor’s stem cell candidates—fibroblasts, typically—may be too set in their epigenetic ways to serve as the basis of new tissues and organs. Or not. That is, some donor fibroblast populations may have relatively weak epigenetic memories. Much depends on the site of origin—the fibroblast’s original location in the body. Another consideration is the donor’s age. If a fibroblast is many divisions removed from its originator cell, it seems to be more crotchety, epigenetically speaking.

These findings emerged from a study conducted by scientists at the Lieber Institute for Brain Development (LIBD). The study, titled "Strong Components of Epigenetic Memory in Cultured Human Fibroblasts Related to Site of Origin and Donor Age," was led by Andrew E. Jaffe, Ph.D., and its relevant findings appeared February 25 in the journal PLOS Genetics.

The study noted that regenerative medicine specialists have been using a type of cell commonly found in the skin called the fibroblast because it is easily obtained from skin samples, grows well in culture, and can be manipulated in the laboratory to de-differentiate into a primordial state known as the induced pluripotent stem cell. These primitive stem cells can then be transformed into mature tissues, such as liver or pancreas cells.

Skin-derived progenitors, however, may receive the highest amount of environmental exposure. The possible detrimental effects of such exposures led the LIBD investigators to compare fibroblast populations that may have been effectively sheltered to different degrees. The LIBD investigators compared fibroblast lines from dura mater of the postmortem brain to those from skin samples in the same individuals.

While the cells appear identical under a microscope, this study identified widespread epigenetic and gene expression differences, suggesting strong epigenetic memory from the cell's original location in the body. In addition, researchers discovered sites that were significantly associated with the age of the donor.

“[We] generated genome-wide DNA methylation and transcriptome data on 11 intrinsically matched pairs of dural and scalp fibroblasts from donors across the lifespan (infant to 85 years),” wrote the authors in PLOS Genetics. “While these cultured fibroblasts were several generations removed from the primary tissue and morphologically indistinguishable, we found widespread epigenetic differences by sampling location at the single CpG, region 'block,' and global spatial scales suggesting a strong epigenetic memory of original fibroblast location.”

“Furthermore,” the authors continued, “many of these epigenetic differences manifested in the transcriptome, particularly at the region-level. We further identified 7,265 CpGs and 11 regions showing significant epigenetic memory related to the age of the donor, as well as an overall increased epigenetic variability, preferentially in scalp-derived fibroblasts—83% of loci were more variable in scalp, hypothesized to result from cumulative exposure to environmental stimuli in the primary tissue.”

The results of this study show there are significant differences in the cells derived from dura vs skin samples across the lifespan. As the field of personalized medicine continues to grow, this evidence necessitates further exploration into the epigenetic patterns in stem cells used for new tissue and organ generation. Additional research is required to determine which cells to cultivate and when, as researchers question how much epigenetic memory is actually erased when creating stem cell models.

"These age-related changes are one of the first examples, to our knowledge, of significant age-related changes in a pure cell population that is many divisions from the original cells," concluded Dr. Jaffe.

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