New insights suggest that the source of human cells used to generate new tissues and organs may be an important consideration in personalized medicine. The Lieber Institute for Brain Development (LIBD) today released the results of a study highlighting molecular differences in cells that are gaining traction in the field of personalized medicine. 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 published in PLOS Genetics.
Significant investments are being made worldwide in precision medicine, concentrated in the curation of stem cell lines for the generation of new tissues and organs. Specialists have primarily relied on skin samples as their source of cells because of the ability of these cells to grow in culture and the relative ease of acquisition and manipulation in the laboratory. As momentum and investment continue to build towards this revolution in personalized medicine, Dr. Jaffe and his team have discovered that both the location and age of cell samples from patients have important considerations when generating patient-specific stem cell lines.
The most popular cell types for generating patient-specific stem cells are skin-derived and therefore receive potentially the highest amount of environmental exposure. 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. Dr. Jaffe noted, “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.”
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.
About this genetics research
Funding: This work was supported by funding from the Lieber Institute for Brain Development. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
This article was submitted directly to NeuroscienceNews.com by Amy Snow Landa. We would like to thank Amy for making us aware of this press release.
Source: Amy Snow Landa – Lieber Institute for Brain Development Image Credit: Image is in the public domain. Original Research: Full open access research for “Strong Components of Epigenetic Memory in Cultured Human Fibroblasts Related to Site of Origin and Donor Age” by Nikolay A. Ivanov, Ran Tao, Joshua G. Chenoweth, Anna Brandtjen, Michelle I. Mighdoll, John D. Genova, Ronald D. McKay, Yankai Jia, Daniel R. Weinberger, Joel E. Kleinman, Thomas M. Hyde, and Andrew E. Jaffe in PLOS Genetics. Published online February 25 2016 doi:10.1371/journal.pgen.1005819
Strong Components of Epigenetic Memory in Cultured Human Fibroblasts Related to Site of Origin and Donor Age
Differentiating pluripotent cells from fibroblast progenitors is a potentially transformative tool in personalized medicine. We previously identified relatively greater success culturing dura-derived fibroblasts than scalp-derived fibroblasts from postmortem tissue. We hypothesized that these differences in culture success were related to epigenetic differences between the cultured fibroblasts by sampling location, and therefore 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). 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 (N = 101,989), region (N = 697), “block” (N = 243), and global spatial scales suggesting a strong epigenetic memory of original fibroblast location. Furthermore, 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. By integrating publicly available DNA methylation datasets on individual cell populations in blood and brain, we identified significantly increased inter-individual variability in our scalp- and other skin-derived fibroblasts on a similar scale as epigenetic differences between different lineages of blood cells. Lastly, these epigenetic differences did not appear to be driven by somatic mutation—while we identified 64 probable de-novo variants across the 11 subjects, there was no association between mutation burden and age of the donor (p = 0.71). These results depict a strong component of epigenetic memory in cell culture from primary tissue, even after several generations of daughter cells, related to cell state and donor age.
“Strong Components of Epigenetic Memory in Cultured Human Fibroblasts Related to Site of Origin and Donor Age” by Nikolay A. Ivanov, Ran Tao, Joshua G. Chenoweth, Anna Brandtjen, Michelle I. Mighdoll, John D. Genova, Ronald D. McKay, Yankai Jia, Daniel R. Weinberger, Joel E. Kleinman, Thomas M. Hyde, and Andrew E. Jaffe in PLOS Genetics. Published online February 25 2016 doi:10.1371/journal.pgen.1005819