A new kind of stem cell?

Scientists at Michigan State University have discovered properties in stem cell "garbage" that may advance regenerative medicine and ways to study birth defects.

Tony Parenti, graduate student in the lab of Amy Ralston PhD, Assistant Professor, Biochemistry and Molecular Biology at Michigan State University (MSU) and co-author with Parenti of the study, found in a sort of stem cell trash pile cells they are calling iXEN cells — a new stem cell.

"Other scientists may have seen these cells before, but considered them defective, or cancer-like," says Parenti. "Rather than ignore these cells that have been mislabeled as waste byproducts, we found gold in the garbage."

The work is published in the journal Stem Cell Reports

A great deal of stem cell research focuses on new ways to make and use pluripotent stem cells.

Pluripotent stem cells are created by "reprogramming" or "inducing" mature (adult) cells back into stem cells. After restarting, induced pluripotent stem cells — or iPS cells, are flexible and thus capable of becoming any cell in the body.

For example, if a patient has a defective liver, healthy cells can be taken from the patient and reprogrammed or induced to become iPS cells. These iPS cells can now assist in regenerating that person's failing liver. Using iPS cells from the same patient also greatly reduces the chance of a patient's body rejecting the "new" cells.

Prior to the creation of iPS cells, scientists developed pluripotent stem cells exclusively from embryos. However, embryos produce not only pluripotent stem cells, but also XEN cells. While pluripotent stem cells can reproduce any cell in the body, XEN cells are less maleable and were thought to be potentially pre-cancerous.

Parenti and team speculated that embryo production of both pluripotent and iXEN cells occurs during the cell reprogramming process.

Their eureka moment came when colonies of iXEN cells were found popping up like weeds in their iPS cell cultures. Using mice as their model animals, the team spent six months proving these genetic weeds were not cancer-like, as previously suspected, but a new kind of stem cell with desirable properties. More surprising, inhibiting expression (or "turning off") XEN genes during reprogramming, decreased production of iXEN cells and increased production of iPS cells.

"Nature makes stem cells perfectly, but we are still trying to improve our stem cell production," says Parenti.

The next step in their research will involve human cells. XEN cells have yet to be discovered in humans, but the possibility for their existence is the team's next focus.

"XEN cells have characteristics that pluripotent stem cells do not have... and can shed light on reproductive diseases.

"If we can continue to unlock the secrets of iXEN cells, we may be able to improve induced pluripotent stem cell quality and lay the groundwork for future research on tissues that protect and nourish the human embryo."

Amy Ralston PhD, Department of Biochemistry and Molecular Biology, Program in Cell and Molecular Biology, Michigan State University, East Lansing, MI, USA, and co-author of the study.

Abtract Introduction
The pluripotency-promoting role of the reprogramming factors OCT4, SOX2, KLF4, and MYC (OSKM) is widely appreciated. However, these reprogramming factors also promote expression of non-pluripotency genes. For example, OCT4 (Pou5f1) directly promotes expression of genes important for mouse primitive endoderm (Aksoy et al., 2013, Frum et al., 2013, Le Bin et al., 2014), an extraembryonic lineage present in the blastocyst, SOX2 indirectly promotes expression of primitive endoderm genes in the mouse blastocyst (Wicklow et al., 2014), KLF4 may regulate expression of primitive endoderm genes in the mouse blastocyst (Morgani and Brickman, 2015), and MYC regulates endodermal genes in fibroblasts and embryonic stem cells (ESCs) (Neri et al., 2012, Smith et al., 2010). These observations raise the possibility that OSKM induce expression of endodermal genes in somatic cells. In support of this idea, several groups have reported that endodermal genes, such as Gata6, Gata4, and Sox17, are upregulated in protocols used to reprogram fibroblasts to induced pluripotent stem cells (iPSCs) (Hou et al., 2013, Serrano et al., 2013, Zhao et al., 2015).

Additional MSU researchers contributing to this study include Keith Latham, Michael Halbisen and Kai Wang.

The National Institutes of Health funded this research through grants R03 HD077112, R01 HD075093, and R01 GM104009.

Michigan State University has been working to advance the common good in uncommon ways for more than 150 years. One of the top research universities in the world, MSU focuses its vast resources on creating solutions to some of the world's most pressing challenges, while providing life-changing opportunities to a diverse and inclusive academic community through more than 200 programs of study in 17 degree-granting colleges.

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Amy Ralston has discovered a new kind of stem cell —
induced extraembryonic endoderm stem (iXEN) cells.
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