Stem cell promise for multiple sclerosis
doi:10.1038/nindia.2011.176 Published online 1 December 2011
New research has found a way to replenish the fatty layer or myelin sheath around nerve cells — a finding that could yield a cure for neurodegenerative diseases such as multiple sclerosis1.
Researchers have now understood how the right mix of biological growth factors coaxes human embryonic stem cells (ESCs) to form oligodendrocytes, a type of nerve cells that form the myelin sheath.
"We have been able to identify the proteins that are expressed during the differentiation of ESCs into oligodendrocyte progenitor cells, which in turn grow into oligodenrocytes," says Akhilesh Pandey, one of the researchers from the Institute of Bioinformatics, Bangalore and Johns Hopkins University School of Medicine, US. "We have also identified several proteins that aid the formation of myelin," he adds.
Oligodendrocytes (OLs) are specialized cells that wrap tightly around axons to form the myelin sheath. The job of these support cells is to speed up the electrical signal that travels down an axon. Without oligodendrocytes an action potential would travel down an axon 30 times slower. Injury to OLs seems to initiate multiple sclerosis. Studies have also shown that OL injury has a role to play in schizophrenia.
The best way to treat such disorders is to replace the worn-out OLs. To achieve this, studies have tried to grow OLs in lab. Oligodendrocyte progenitor cells (OPCs) have been grown from human ESCs in animals with spinal cord injury and multiple sclerosis. Lab studies have discovered a number of growth factors, which promote OPC migration, survival and proliferation. Despite identifying factors that affect OPC proliferation and differentiation, researchers knew little about the factors that trigger myelin-forming OLs.
To zero in on proteins specific to OL differentiation, the researchers grew human ESCs in a nutrient broth laced with various growth factors. They observed the proliferation and differentiation of ESCs into embryoid bodies, neural progenitor cells (NPCs), glial progenitor cells (GPCs) and OPCs which could finally grow into OLs and form myelin. At every stage of cell differentiation, the researchers harvested cells and identified stage-specific proteins using state-of-the-art mass spectrometry analysis.
The study identified 3145 proteins at key stages of OL differentiation from human ESCs. Some of the vital proteins at the OPC stage were neural cell adhesion molecule 1 (NCAM1), APOE, tenascin C (TNC), vimentin (VIM), wingless-related MMTV integration site 5A (WNT5A), and heat shock 27 kDa protein 1.
"Further exploration of these proteins within the OL lineage is likely to yield novel therapies for diagnosing and treating many OL-associated or demyelinating conditions," Pandey says.
The study also found novel markers for NPCs and GPCs which would add to the repertoire of specific markers increasing specificity. The NPCs can differentiate in neural and glial cells. "The multiple markers will aid in selection of pure cells, which is currently a limiting factor", Pandey adds.
There is no single specific marker for a stem cell. "The study affords a group of protein markers for the identification of a cell type. Such identification will provide valuable clues for future studies about the pathways involved in the transformation of the ESCs into progenitor cells," says Sumantra Das who studies neurobiochemistry and neuropharmacology at Indian Institute of Chemical Biology, Kolkata.
Though the study identifies molecular markers in a single shot, the question is how far the information is valuable since artificial progenitor cells generated may not be phenotypically similar to a primary progenitor cell isolated from the brain, Das says.
"The study offers a comprehensive base line molecular data in normal embryonic stem cells and pluripotent neural, glial and oligodendroglial cells in a culture medium," says S. K. Shankar from the National Institute of Mental Health and Neuro Sciences, Bangalore. However, similar information in an animal system and isolation of cells at different lineages from intact organ are important for extrapolation, Shankar told Nature India.
- Chaerkady, R. et al. Quantitative temporal proteomic analysis of human embryonic stem cell differentiation into oligodendrocyte progenitor cells. Proteomics. 11, 4007-4020 (2011)