Stem Cell Report – February 2001

Date: 03/02/2001

Embryonic stem cells prove disappointing…

Researchers continue to show scant success in moving embryonic stem (sometimes termed human pluripotent) cells closer to clinical trials. Noting recent advances using adult stem cells, an article in Science (12/1/00) said: “In contrast, the human embryonic stem cells and fetal germ cells that made headlines in November 1998 because they can, in theory, develop into any cell type have so far produced relatively modest results. Only a few papers and meeting reports have emerged from the handful of labs that work with human pluripotent cells.”

In October scientists at The Hebrew University in Jerusalem, in collaboration with a scientist at Harvard University, tried to produce specialized cell types in culture by using combinations of 8 specific growth signals. They report: “The work presented here shows that none of the eight growth factors tested directs a completely uniform and singular differentiation of cells.” “The work suggests that it will not be simple to produce the pure populations of certain cell types that would be required for safe and reliable cell therapies–much less the hoped-for replacement organs,” says stem cell researcher Oliver Brüstle of the University of Bonn in Germany. “At present, it looks like it is really difficult to differentiate these [embryonic] cells into more advanced cell types.” “Simply keeping human embryonic stem cells alive can be a challenge,” says Peter Andrews of the University of Sheffield in England. “They’re tricky.” Douglas Melton of Harvard University uses almost the same words: “Human embryonic stem cells ‘are trickier than mouse.’ They’re more tedious to grow.”

The Science article further notes that scientists at Geron Corp. in Menlo Park, California, who have been working with human embryonic stem cells longer than anyone, are no closer than other scientists to devising therapeutic uses for them. “Geron researchers reported last month at the annual meeting of the Society of Neuroscience that they had attempted to transplant human embryonic stem cells into rats. When they injected undifferentiated cells into the brain, they did not readily differentiate into brain cells, the researchers found. Instead, they stayed in a disorganized cluster, and brain cells near them began to die. Even partially differentiated cells, the team reported, tended to clump together; again, nearby brain cells died.”

Researchers at Johns Hopkins have also experienced difficulties. Led by John Gearhart, who originally grew human embryonic germ cells from fetal tissue, they have had to alter the original cells, forming what are termed “embryoid body-derived” (EBD) cells. “The EBDs reproduce readily and are easily maintained,” Gearhart said, “and thus eliminate the need to use fetal tissues each time as a source.” “We thought from the first that problems would arise using hPSCs [human pluripotent stem cells] to make replacement tissues,” says molecular biologist Michael Shamblott, Ph.D. The early-stage stem cells are both difficult and slow to grow. “More important,” says Shamblott, “there’s a risk of tumors. If you’re not very careful when coaxing these early cells to differentiate – to form nerve cells and the like — you risk contaminating the newly differentiated cells with the stem cells. Injected into the body, stem cells can produce tumors. The EBDs bypass all this.”1

…While adult stem cells advance toward treating degenerative neural disorders

Scientists have found that cultures of adult stem cells from spinal cord can be grown from single cells, and can differentiate into neural cells when injected into the spinal cord or brain of rats. The researchers noted that the adult stem cells generate region-specific neurons in the body when exposed to the appropriate environment.

Two research groups have shown that adult bone marrow stem cells can be injected into the bloodstream and migrate to the brain, where they become incorporated into brain tissue and differentiate into neurons. One group noted that generation of brain cells from adult bone marrow “demonstrates a remarkable plasticity of adult tissues with potential clinical applications.” The other research team said: “These findings raise the possibility that bone marrow-derived cells may provide an alternative source of neurons in patients with neurodegenerative diseases or central nervous system injury.”

Researchers in the UK have shown that brain cells called “oligodendrocytes” can be “reprogrammed”, forming complete adult neural stem cells which can generate multiple brain cell types. The scientists found that different combinations of growth signals could cause the cells to revert to a multipotential adult stem cell, and note that “these precursor cells have greater developmental potential than previously thought.”

Research at the University of California-Irvine College of Medicine shows that simply adding the proper growth signal to injured brains may be sufficient to stimulate the neural stem cells already in the brain, rescuing brain cells. The researchers note that this “points as a means of treating the cholinergic component of neuronal loss in Alzheimer’s disease.”

Another report from the University of California-Irvine showed that infusion of a single factor named transforming growth factor alpha into rats with brain damage similar to Parkinson’s induced rapid proliferation of neural stem cells, followed by their migration and differentiation into neurons. Treated rats had decreased symptoms. The scientists note: “This finding has significant implications with respect to the development of treatments for both acute neural trauma and neurodegenerative diseases,” and: “The data predict an alternative strategy to the current cell transplant methodologies for the treatment of neurodegenerative diseases.”2

Sonic Hedgehog” Paves Way for Potentially Unlimited Supplies of Adult Stem Cells; Improved Treatment for Cancer Patients

Canadian scientists have identified a way to make adult stem cells grow in the laboratory in much the same way as they do in the developing human embryo. Adult bone marrow stem cells and cord blood cells, when treated with a naturally-occurring protein, grow in culture similar to the way that embryonic stem cells grow. The protein, dubbed “sonic hedgehog,” by its discoverer, stimulates growth of significant quantities of adult stem cells. The finding could have immediate application for cancer treatments, in which patients undergo chemotherapy or radiation treatments to kill the cancer, and are then given back their own adult stem cells to replace their immune system.3

  1. M. Schuldiner et al.; “Effects of eight growth factors on the differentiation of cells derived from human embryonic stem cells Proc. Natl. Acad. Sci. USA 97, 11307-11312; Oct. 10, 2000; G. Vogel; “Stem cells: New excitement, persistent questions Science 290, 1672-1674; Dec 1 2000; M.J. Shamblott, J. Axelman, J.W. Littlefield, P.D. Blumenthal, G.R. Huggins, Y. Cui, L. Cheng, J.D. Gearhart; “Human embryonic germ cell derivatives express a broad range of developmentally distinct markers and proliferate extensively in vitro Proc Natl Acad Sci USA 98, 113-118; Jan 2 2001; Johns Hopkins Medical Institutions Office of Communications and Public Affairs; “New Lab-Made Stem Cells May Be Key To Transplants Dec. 25 2000.
  2. S. Shihabuddin et al.; “Adult spinal cord stem cells generate neurons after transplantation in the adult dentate gyrus J Neuroscience 20, 8727-8735; December 2000; T.R. Brazelton et al.; “From marrow to brain: expression of neuronal phenotypes in adult mice Science 290, 1775-1779; Dec 1, 2000; E. Mezey E et al.; “Turning blood into brain: Cells bearing neuronal antigens generated in vivo from bone marrow Science 290, 1779-1782; Dec 1, 2000; T. Kondo, and M. Raff; “Oligodendrocyte precursor cells reprogrammed to become multipotent CNS stem cells Science 289, 1754-1757; Sept. 8, 2000; M.H. Tuszynski; “Intraparenchymal NGF infusions rescue degenerating cholinergic neurons Cell Transplant 9; 629-636; Sept-Oct 2000; J. Fallon et al.; “In vivo induction of massive proliferation, directed migration, and differentiation of neural cells in the adult mammalian brain Proc. Natl. Acad. Sci. USA 97, 14686-14691; December 19, 2000.
  3. G. Bhardwaj et al.; “Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation Nature Immunology 2, 172-180; Feb 2001.
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