Human stem/progenitor cells from bone marrow promote neurogenesis of endogenous neural stem cells in the hippocampus of mice

Abstract

Stem/progenitor cells from bone marrow and other sources have been shown to repair injured tissues by differentiating into tissue-specific phenotypes, by secreting chemokines, and, in part, by cell fusion. Here we prepared the stem/progenitor cells from human bone marrow (MSCs) and implanted athem into the dentate gyrus of the hippocampus of immunodeficient mice. The implanted human MSCs markedly increased the proliferation of endogenous neural stem cells that expressed the stem cell marker Sox2. Labeling of the mice with BrdUrd demonstrated that, 7 days after implantation of the human MSCs, BrdUrd-labeled endogenous cells migrated throughout the dorsal hippocampus (positive for doublecortin) and expressed markers for astrocytes and for neural or oligodendrocyte progenitors. Subpopulations of BrdUrd-labeled cells exhibited short cytoplasmic processes immunoreactive for nerve growth factor and VEGF. By 30 days after implantation, the newly generated cells expressed markers for more mature neurons and astrocytes. Also, subpopulations of BrdUrd-labeled cells exhibited elaborate processes immunoreactive for ciliary neurotrophic factor, neurotrophin-4/5, nerve growth factor, or VEGF. Therefore, implantation of human MSCs stimulated proliferation, migration, and differentiation of the endogenous neural stem cells that survived as differentiated neural cells. The results provide a paradigm to explain recent observations in which MSCs or related stem/progenitor cells were found to produce improvements in disease models even though a limited number of the cells engrafted.

Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain

“…51 To further substantiate this hypothesis, it should be noted that studies have shown that inflammatory processes have a negative effect on cell proliferation. 52,53 As such, molecular and behavioral recovery can be stimulated despite the fact that, as a result of the inflammatory and rejection processes, many of the transplanted cells are eventually absorbed by the host immune system.…”

Mesenchymal Stem Cells Shape Microglia Effector Functions Through the Release of CX3CL1

“…Moreover, MSC can protect axons and improve neuronal survival [4,9,10] releasing antiapoptotic [11] or antioxidant molecules [12]. It has been also reported that MSC may foster endogenous neurogenesis [13] and oligodendrogenesis [14][15][16] not only by direct release of trophic factors but also by stimulating glial cells to secrete molecules leading to neuron survival and proliferation of the endogenous neural precursor cells [17].…”

Mesenchymal stem cells increase hippocampal neurogenesis and counteract depressive-like behavior

“…14,21 Similarly, injection of human MSCs into the hippocampus of normal mice resulted in a significant increase in neurogenesis, originating primarily from host neural stem cells. 8 Moreover, the engraftment of neural stem cells or MSCs in the hippocampus and dentate gyrus resulted in increased neurogenesis and induced an improved behavioral phenotype in prenatal heroin exposure and in apolipoprotein E knockout mice, respectively. 22,23 In this study, we therefore analyzed the possible therapeutic potential of MSCs in depression.…”

“…7 Moreover, transplantation of MSCs in the central nervous systems prevents apoptosis and promotes neurogenesis (proliferation and differentiation) of 'host' neural cells and stem cells in the engrafted site. [7][8][9] MSCs were therefore suggested as candidates for treating a variety of neurodegenerative diseases, in particular Parkinson's disease, multiple sclerosis, cerebral hemorrhage and brain cancer. [10][11][12][13] Neurogenesis is a continuous process of the formation of new neurons, which occurs in the dentate gyrus in the hippocampus throughout life.…”