Indian stem cell scientists find clues to birth defects

By Papri Sri Raman, IANS

Chennai : In a discovery that could have a far-reaching impact on the development of drugs, scientists in Karnataka’s Manipal town have for the first time found clues to how defects occur during foetal growth.

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Researchers from the Manipal Institute of Regenerative Medicine have discovered that the presence of very low amounts of an endotoxin, a potentially toxic natural compound, in the foetal environment can cause defects in the development of tissues in a growing foetus.

Gram-negative bacterial lipopolysaccahrides (LPS) are the main antigenic components of the cell wall of harmful bacteria that cause vaginosis, which is a common bacterial infection of the maternal genital tract.

LPS, which is harmful for foetuses, is regularly shed in the environment where the embryo grows when the mother is suffering from vaginosis.

Silent infections of gram-negative bacteria like Chlamydia trachomatis can also cause birth defects with poorly developed tissues and organs of the foetus.

An understanding of the molecular mechanisms of such pathogenesis remains obscure owing to ethical issues dogging the use of human embryos in research.

“We have, therefore, used embryoid bodies as a tool to understand the effect of endotoxins on the induction of lineages in a developing foetus,” Kaushik Deb, principal scientist of the Manipal Institute’s embryonic stem cell programme and chief researcher of the team, told IANS.

Embryonic stem cells provide a reliable source for studying the formation of all the 220 different tissues of the human body.

Scientists said these cells could be grown as cultures in petri dishes to produce early embryo-like entities, known as embryoid bodies (EBs), which consist of a differentiated population of cells representing all the germ layers – ectoderm, endoderm and mesoderm.

These EBs closely mimic a growing embryo in a mother’s womb.

During their one and a half years of research work, the Manipal team found that “a molecular analysis of the EBs from the mesoderm region exposed to LPS indicated the complete silencing of expression for eight kinds of tissue markers”, Deb explained.

“These EBs were then tested for their ability to produce bone tissues of mesoderm origin. As expected, these EBs could not be differentiated to primary bone tissue. They had lost their ability to form functional bone cells due to LPS exposure,” he said.

How LPS affects different kinds of tissue formation was then studied in greater detail.

Based on their findings, the researchers have suggested that LPS induced HMGB1 protein is involved in the specific silencing of tissue differentiation in stem cells.

“Human embryonic stem cells are the gold standard for studying tissue formation and enable us to predict the effect of various pharmaceuticals and natural toxins that the growing foetus may accidentally get exposed to while inside the womb,” Deb added.

Satish Totey, chief scientific officer of Stempeutics Research Pvt. Ltd – a stem cell research company that has supported and partially funded the research work, said: “These findings have significant implications for birth defect research and evaluation of developmental toxicity during drug screening.”

The findings of the Indian scientists have been published in the January 2008 edition of Regenerative Medicine journal.

Stephen Minger, chief editor of the journal and director of the stem cell laboratory of King’s College, London, said: “Trace amounts of LPS in the embryo culture media used during in-vitro fertilisation (IVF) can lead to poor pregnancy outcome.

“Also, if the embryos are transferred to a mother with bacterial vaginosis, the pregnancy could lead to a child with weak formation of bone, blood or even heart tissues.”