24 Jun 2002

The current on-line edition of Nature features two reports on generating functional adult cells, including neurons, from stem cells.

Catherine Verfaillie and colleagues at the University of Minnesota in Minneapolis found a rare type of mesenchymal stem cell in adult mouse and rat bone marrow that retains the ability to differentiate along other mesodermal pathways, but also along endodermal and ectodermal pathways. In the presence of neural signaling molecules, these mesanchymal adult progenitor cells (MAPCs) could be induced to become neural-like cells, many of which expressed markers indicative of serotonergic, dopaminergic, or GABAergic neurons. They had polar structures with tau-containing axon-like processes and MAP2-containing somatodendritic compartments.

In a second round of experiments, Jiang et al. injected MAPCs injected into 3.5-day-old blastocysts. Most animals killed at 6-20 weeks contained the progeny of MAPCs along with their own cells. The "foreign" cells were distributed throughout many tissues, including the brain, where the authors spotted both neurons and glia derived from the injected MAPCs. Interestingly, the majority of granule cells of the hippocampal dentate gyrus were derived from the mesenchymal stem cells.

Finally, the authors injected MAPCs into the blood of adult animals. They again found evidence of incorporation in a variety of tissues, though not in brain, where the blood-brain barrier would keep out anything as large as a cell floating by.

Adult-derived stem cells like MAPCs have potential advantages over embryonic stem (ES) cells, not the least of which is the ethical storm surrounding the use of 5-day-old human embryos to derive ES cells. However, ES cells have the advantage of unlimited proliferation in culture and may offer more potential for genetic manipulations to ensure the appropriate development of particular cell types.

In the other report, Ron McKay and colleagues at the National Institute of Neurological Disorders and Stroke, in Bethesda, Maryland, sought to overcome the problem that existing generation of dopaminergic (DA) neurons ES cells is unreliable. Kim et al. increased the likelihood of producing DA cells by introducing the transcription factor nuclear receptor-related 1( Nurr1) into the genome of mouse ES cells. They further encouraged differentiation into DA cells by treating the cultures with fibroblast growth factor 8 (FGF8) and sonic hedgehog (SHH), which are essential for the differentiation of DA cells in the midbrain in vivo.

With these manipulations, they nudged about 80 percent of their ES cells into becoming fully functional dopamine-releasing cells. When the cells were grafted into a Parkinson's disease model (6-hydroxy-dopamine lesioned mice), they survived, extended axons into the host animal's striatum (the target of substantia nigra dopamine neurons lost in PD), and formed functional synapses. The grafted cells' performance under electrophysiological recording was similar to that of endogenous dopamine neurons. Finally, lesioned mice with grafts performed significantly better than lesioned, non-grafted mice on a number of motor assessments used in PD models, the authors write.

A concern with ES cell grafts is that they have shown a propensity to develop tumors. In this study, McKay's team found no evidence of continuing cell division within the grafts up to 8 weeks after surgery.—Hakon Heimer

Comments

1. • Kiminobu Sugaya
     University of Central Florida
   • Posted: 24 Jun 2002

   The Verfaillie paper reports the identification of pluripotent adult stem cells, which may serve as an alternative to embryonic stem cells as transplant material for cell replacement therapy. Although the paper's title refers to this cell as equivalent to mesenchymal stem cells, it could provide progenitors for mesenchymal and hematopoietic cells. The multipotency of mesenchymal stem cells has been discussed for a long time.

   This report details a series of extensive studies from in vitro to in vivo. The characteristics and functions of a sub-population of bone marrow stem cells are quite similar to those of embryonic stem cells in that they responded to treatment with the same factors in vitro. This suggests that the "multipotent adult progenitor cells" did not differentiate to tissue-specific stem cells by responding to the environment or that adult bone marrow has environmental conditions similar to the inside of the blastocyst. Curiously, the cells did not develop a typical neural differentiation after transplantation to the postnatal animal. Since factors needed for neurogenesis may continue to be expressed in the postnatal animal, this issue needs to be explained. In summary, these cells have great potential, but I would like future studies to show their neural differentiation in the adult brain in before "multipotent adult progenitor cells" are applied to neuroreplacement strategies.

   The McKay article pushes the envelope of embryonic stem cells in neuroreplacement strategies further. This study has overcome two hurdles: it differentiated embryonic stem cells into neural cells, and it generated from these a specific type of neuron (dopaminergic). Each experiment elegantly proceeds from in vitro differentiation to the assessment of in vivo physiological function including a behavioral test.

   Transplanted cells survived for 8 weeks without changing their numbers, indicating no tumorigenesis. I like the idea of transfecting Nurr-1into embryonic stem cells, a transcription factor that induces dopaminergic differentiation in midbrain precursor cells. This approach may be useful to induce other specific types of differentiation in the stem cells.

   The only down side I see with this study is that they transplanted the cell into the striatum, the projection area of the dopaminergic cells in the substantia nigra (SN). To aim at full integration of the transplanted cell into the host brain, neuroreplacement ultimately has to be done in SN. Otherwise, cells transplanted to the striatum may become uncontrolled and cause side effects, as we have seen in several fetal tissue transplant studies. I would like to see SN cell replacement and a trial with other types of stem cell using similar tactics in the future.

   View all comments by Kiminobu Sugaya

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