In the issue of G&D, Dr. K. John McLaughlin and colleagues report on their success in using uniparental embryonic stem cells to replace blood stem cells in mice. Uniparental embryonic stem cells are an appealing alternative source of patient-derived embryonic stem cells, as they have several advantages over embryonic stem cell lines generated by somatic cell nuclear transfer (also known as therapeutic cloning).
Normal mammalian embryos inherit one set of chromosomes from the mother, and one set from the father. Embryos that inherit both sets of chromosomes from the same parent are not viable. They can, however, generate "uniparental" embryonic stem cell lines. Uniparental embryos with two maternal sets of chromosomes are known as parthenogenetic. These embryos have been considered a potential source of embryonic stem cell derived tissues for transplantation into the female from which they were derived.
This study shows for the first time that parthenogenetic blood cells can replace those of an immunocompromised adult mouse. McLaughlin and colleagues also show that this is also possible using embryonic stem cells where both genomes are solely derived from sperm of one male (androgenetic), adding fertile males to the potential patient pool.
Since uniparental ES cells are not derived from viable embryos, their harvesting and use sidesteps many of the ethical concerns that plague traditional ES cell therapies. However, uniparental ES cell research faces the biological hurdle of genomic imprinting, in which specific gene expression patterns are dictated by the parental origin. Uniparental cells only have the imprinting marks for one parental type (or "from one parent") with unknown consequences if harvested and transplanted into adults.
Previous work has shown that uniparental ES cells have only limited ability to contribute to fetal and postnatal development in chimeric animals, with androgenetically-derived uniparental ES cell chimeras displaying abnormal phenotypes and increased lethality. In their current paper, Dr. McLaughlin and colleagues tested the functionality of uniparental ES cells in adult tissues.
"It has been known for over a decade that uniparental cells had some capacity to form tissues in vitro and in vivo but it was questionable if these embryonic stem cells could generate transplantable material that would proliferate and replace tissues in an adult."
The researchers took a two-step approach: First they injected uniparental ES cells into wild-type blastocyts to generate chimeric animals; then they harvested these chimeric fetal livers for transplant into lethally irradiated hosts. The scientists found that uniparental ES cells, regardless of parent-of-origin, were able to functionally reconstitute the entire hematopoietic system of adult mice. Furthermore, the scientists were also able to grow progenitor blood cells in culture from uniparental ES cells, and upon transplant into irradiated adult mice, show that these cells contribute, long-term, to the function of their hematopoietic system.
One issue in using uniparental ES cells for tissue transplants is their durability and safety. McLaughlin's group were able to maintain animals for over 12 months with entirely uniparental blood and were able to rescue irradiated mice with bone marrow transplants from these animals. This unambiguously proves that the transplanted uniparental cells could produce hematopoietic stem cells.
"The ability of the "sperm derived" androgenetic cells to replace adult blood was totally unexpected based on what occurs with these cells during development. The male derived androgenetic cells were at least as effective as the maternal derived cells."
Dr. McLaughlin's new paper expands the horizons for regenerative medicine, not only by demonstrating that uniparental stem cells can form adult-transplantable progenitor cells in cell culture, but also by illustrating the potential utility of androgenetic, as well as parthenogenetic ES cells.