Comment |
Address correspondence to Jonas Frisén, Department of Cell and Molecular Biology, Medical Nobel Institute, SE-171 77 Stockholm, Sweden. Tel.: (46) 872-87562. Fax: (46) 834-8135. E-mail: jonas.frisen{at}cmb.ki.se
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Stem cells in adult mammals have lately started showing off some unexpected talents. Stem cells from several adult organs, such as brain and bone marrow, seem to ignore cell lineage restrictions and may not be as rigid in their fate choices as we previously thought. Several studies have shown that stem cells feature a previously unknown plasticity to adapt to the microenvironment regardless of germ layer origin (Bjornson et al., 1999; Clarke et al., 2000; Clarke and Frisén., 2001; Krause et al., 2001; Morrison, 2001).
![]() |
Bone marrow off the beaten path |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Brainy marrow |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
A new effort was undertaken to study phenotypic conversions of bone marrow cells, and this time preliminary evidence pointed to neurons (Mezey and Chandross, 2000). Mice homozygous for a mutation in the PU.1 gene were irradiated and used as bone marrow recipients. When analyzing the brains of these mice after transplantation, unexpectedly, 5% of the total amount of brain cells and 12% of all cells expressing the neuronal marker NeuN were derived from the grafted bone marrow. However amazing and hard to grasp, these results have been corroborated by two more thorough studies (Brazelton et al., 2000; Mezey et al., 2000). Mezey and colleagues found that 2.34.6% of the transplant recipients brains were bone marrowderived, and that 0.32.3% of these cells expressed neuronal markers (NeuN or neuron-specific enolase) after grafting. Most of the presumptive bone marrowderived neurons were found in the cerebral cortex, and they were also present in the hypothalamus, hippocampus, amygdala, periaqueductal gray, and striatum. The study by Helen Blau's group reached the same conclusion and reported that 0.20.3% of the total number of neurons in the olfactory bulb were derived from the bone marrow by 812 wk after transplantation. In the latter study, three neuronal markers were used, NeuN, type III ß-tubulin, and neurofilament, as well as the phosphorylated form of CREB as support for a neuronal identity of the cells.
![]() |
The bloody neurons show their true colors |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In spite of these somewhat discouraging findings, Priller and colleagues went on to analyze other mice at much longer survival times after the bone marrow transplantation. Astonishingly, they then found highly differentiated bone marrowderived neurons in the cerebellum. These neurons had the typical morphology and marker profile of Purkinje cells. At 1215 mo after transplantation, up to 0.1% of the Purkinje cells derived from bone marrow cells by virtue of their eGFP expression. This neuronal type is characterized by its extremely elaborate processes, and the generation of one of the more complex neuronal morphologies by a bone marrowderived cell is a true tour de force. Although there is a continuous generation of neurons in certain parts of the adult mammalian brain, the genesis of this neuronal type has never been described in adulthood. However, the methods used to study adult neurogenesis would be unlikely to detect such a rare event. Interestingly, adult-generated neurons are typically interneurons with short processes, which may be related to the great challenge it must be to grow and extend long processes to a distant target within the adult brain. In light of this challenge, it is truly astonishing that Purkinje cells, with their long processes, can be generated in adulthood. The authors also provide ultrastructural evidence for synaptic integration of the bone marrowderived Purkinje cells, suggesting that they may become functionally integrated in the circuitry of the adult brain.
![]() |
How many neurons derive from the bone marrow? |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
How can these data then be reconciled? Differences in the experimental design between the studies may, at least in part, account for the discrepancies. Another possible explanation, supported by data from the new report, is that the bone marrowderived cells, shortly after the transplantation, may start differentiating toward a neuronal phenotype but die before reaching full maturation, perhaps due to limited functional integration and trophic support.
It is also important to consider that the conclusions of the previous studies have rested on the detection of neuron-specific antigens in bone marrowderived cells. Some of these markers may be less reliable than we previously thought and can occasionally be found on cells that lack other neuronal features, such as for example synapses, typical electrophysiological properties or a mature neuronal morphology. Thus, the expression of certain proteins does not necessarily reflect a functional conversion to a mature neuronal phenotype. Another possibility, which has not yet been fully ruled out, is that localization of neuronal markers to bone marrowderived cells could be a result of bone marrowderived cells phagocytosing neurons (which may be dying due to the irradiation preceding the transplantation), and in that way transiently acquire neuronal proteins.
The present work does support the idea that a subpopulation of bone marrow cells actually can generate new neurons by providing persuasive morphological evidence. This means that at least some bone marrowderived cells that are identified as neurons by the expression of a few neuronal proteins indeed exhibit all the morphological characteristics of a mature neuron, such as an axon, dendrites, and synapses, giving very strong support to the concept of bone marrowderived neurons.
![]() |
How and why? |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Second, do bone marrow cells generate neurons under physiological conditions, or is this a result of the contrived experimental situations that have been used to study and establish this phenomenon? In all these studies the bone marrow transplant recipient mice have been compromised either by irradiation or by a genetic defect, which is necessary for the bone marrow transplant to take. Methods to label endogenous bone marrow cells in a minimally traumatic way will be necessary to elucidate whether this cellular exchange is an innate physiological process.
Third, what is the functional significance of the process? It is difficult to imagine that the exchange of 0.1% of Purkinje cells may have a discernable impact on brain function. However, the much higher numbers indicated by the previous studies may no doubt have a significant impact. Loss-of-function experiments will be needed to establish the physiological role and to answer whether the ablation of this process leads to any functional deficit.
![]() |
The cell biology of lineage infidelity |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
A third possibility is that a committed stem or progenitor cell, in a new environment and influenced by local cues, takes on the identity of a stem or progenitor cell of that tissue. This would not, strictly speaking, be a case of transdifferentiation, which requires the cell swapping phenotype to be differentiated. A stem or progenitor cell switching lineage could perhaps be thought of as transcommitment. In this model, stem cells in different tissues would be able to adapt to a new niche in an unrelated tissue and generate the type of differentiated cells appropriate for the new context.
The question of how the differentiated state is maintained and reversed is a key question in biology today, the elucidation of which promises to bring insight into physiology and may teach us how to control cell differentiation in therapeutic situations.
![]() |
Acknowledgments |
---|
Work described from the authors' laboratory was funded by grants from the Swedish Foundation for Strategic Research, the Swedish Medical Research Council, the Karolinska Institute, and the Swedish Cancer Foundation.
Submitted: 30 October 2001
Accepted: 31 October 2001
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Alison, M.R., R. Poulsom, R. Jeffery, A.P. Dhillon, A. Quaglia, J. Jacob, M. Novelli, G. Prentice, J. Williamson, and N.A. Wright. 2000. Hepatocytes from non-hepatic adult stem cells. Nature. 406:257.[Medline]
Baron, M.H., and T. Maniatis. 1986. Rapid reprogramming of globin gene expression in transient heterokaryons. Cell. 46:591602.[Medline]
Bjornson, C.R., R.L. Rietze, B.A. Reynolds, M.C. Magli, and A.L. Vescovi. 1999. Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo. Science. 283:534537.
Brazelton, T.R., F.M. Rossi, G.I. Keshet, and H.M. Blau. 2000. From marrow to brain: expression of neuronal phenotypes in adult mice. Science. 290:17751779.
Brockes, J.P. 1997. Amphibian limb regeneration: rebuilding a complex structure. Science. 276:8187.
Clarke, D.L., and J. Frisén. 2001. Differentiation potential of adult stem cells. Curr. Opin. Genet. Dev. 11:575580.[Medline]
Clarke, D.L., C.B. Johansson, J. Wilbertz, B. Veress, E. Nilsson, H. Karlstrom, U. Lendahl, and J. Frisen. 2000. Generalized potential of adult neural stem cells. Science. 288:16601663.
Doetsch, F., I. Caille, D.A. Lim, J.M. Garcia-Verdugo, and A. Alvarez-Buylla. 1999. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell. 97:703716.[Medline]
Eglitis, M.A., and E. Mezey. 1997. Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc. Natl. Acad. Sci. USA. 94:40804085.
Ferrari, G., G. Cusella-De Angelis, M. Coletta, E. Paolucci, A. Stornaiuolo, G. Cossu, and F. Mavilio. 1998. Muscle regeneration by bone marrow-derived myogenic progenitors. Science. 279:15281530.
Gussoni, E., Y. Soneoka, C.D. Strickland, E.A. Buzney, M.K. Khan, A.F. Flint, L.M. Kunkel, and R.C. Mulligan. 1999. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature. 401:390394.[Medline]
Jackson, K.A., S.M. Majka, H. Wang, J. Pocius, C.J. Hartley, M.W. Majesky, M.L. Entman, L.H. Michael, K.K. Hirschi, and M.A. Goodell. 2001. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J. Clin. Invest. 107:13951402.
Johansson, C.B., S. Momma, D.L. Clarke, M. Risling, U. Lendahl, and J. Frisen. 1999. Identification of a neural stem cell in the adult mammalian central nervous system. Cell. 96:2534.[Medline]
Krause, D.S., N.D. Theise, M.I. Collector, O. Henegariu, S. Hwang, R. Gardner, S. Neutzel, and S.J. Sharkis. 2001. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell. 105:369377.[Medline]
Lagasse, E., H. Connors, M. Al-Dhalimy, M. Reitsma, M. Dohse, L. Osborne, X. Wang, M. Finegold, I.L. Weissman, and M. Grompe. 2000. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat. Med. 6:12291234.[Medline]
Mezey, E., and K.J. Chandross. 2000. Bone marrow: a possible alternative source of cells in the adult nervous system. Eur. J. Pharmacol. 405:297302.[Medline]
Mezey, E., K.J. Chandross, G. Harta, R.A. Maki, and S.R. McKercher. 2000. Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science. 290:17791782.
Morrison, S.J. 2001. Stem cell potential: can anything make anything? Curr. Biol. 11:R7R9.[Medline]
Morrison, S.J., N. Uchida, and I.L. Weissman. 1995. The biology of hematopoietic stem cells. Annu. Rev. Cell Dev. Biol. 11:3571.[Medline]
Orlic, D., J. Kajstura, S. Chimenti, I. Jakoniuk, S.M. Anderson, B. Li, J. Pickel, R. McKay, B. Nadal-Ginard, D.M. Bodine, et al. 2001a. Bone marrow cells regenerate infarcted myocardium. Nature. 410:701705.[Medline]
Orlic, D., J. Kajstura, S. Chimenti, F. Limana, I. Jakoniuk, F. Quaini, B. Nadal-Ginard, D.M. Bodine, A. Leri, and P. Anversa. 2001b. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc. Natl. Acad. Sci. USA. 98:1034410349.
Pavlath, G.K., and H.M. Blau. 1986. Expression of muscle genes in heterokaryons depends on gene dosage. J. Cell Biol. 102:124130.[Abstract]
Petersen, B.E., W.C. Bowen, K.D. Patrene, W.M. Mars, A.K. Sullivan, N. Murase, S.S. Boggs, J.S. Greenberger, and J.P. Goff. 1999. Bone marrow as a potential source of hepatic oval cells. Science. 284:11681170.
Priller, J., D. Persons, F.F. Klett, G. Kempermann, G.W. Kreutzberg, and U. Dirnag. 2001. Neogenesis of cerebellar Purkinje neurons from gene-marked bone marrow cells in vivo. J. Cell Biol. 733738.
Prockop, D.J. 1997. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science. 276:7174.
Theise, N.D., M. Nimmakayalu, R. Gardner, P.B. Illei, G. Morgan, L. Teperman, O. Henegariu, and D.S. Krause. 2000. Liver from bone marrow in humans. Hepatology. 32:1116.[Medline]
|
|