Molecular pathways involved in neural in vitro differentiation of marrow stromal stem cells

Abstract

In recent years several reports have claimed to demonstrate trans-differentiation, namely that stem cells have been derived from a given tissue and have differentiated into phenotypes characteristic of different tissues following transplantation or in vitro treatment. For example, the mesenchymal stem cells, also referred to as marrow stromal stem cells (MSCs), present in bone marrow, have been induced to differentiate into neurons. We decided to investigate this phenomenon more in depth by a molecular and morphological follow-up. We analyzed the biochemical pathways that are currently induced to trigger neuron-like commitment and maturation of MSCs. Our studies suggest that: (i) the increase in cAMP, induced to differentiate MSCs, activates the classical PKA pathway and not through the exchange protein directly activated by cAMP (EPAC), a guanine nucleotide exchange factor for the small GTPase Rap1 and Rap2; (ii) MEK-ERK signaling could contribute to neural commitment and differentiation; (iii) CaM KII activity seems dispensable for neuron differentiation. On the contrary, its inhibition could contribute to rescuing differentiating cells from death. Our research also indicates that the currently used in vitro differentiation protocols, while they allow the early steps of neural differentiation to take place, are not able to further sustain this process.

Ex vivo expansion and pluripotential differentiation of cryopreserved human bone marrow mesenchymal stem cells

“…These include retinoic acid (Cho et al, 2005), DMSO and BHA (Chu et al, 2004;Lu et al, 2004), GM1 and bFGF (Dezawa et al, 2004;Zhang et al, 2004b;Munoz-Elias et al, 2003), and 2-mercaptoethanol (2-ME) (Guo et al, 2001). It was suggested that cAMP signaling pathway should be involved in neurocytic differentiation of MSCs (Suon et al, 2004;Jori et al, 2005), but it could not rule out the synergistic effect of other signaling pathways on neurogenesis of hMSCs, in regard to neural differentiation of embryonic stem cells (Kleber et al, 2005;Bainter et al, 2001;Otero et al, 2004). Neuhuber et al(2004) highlighted the possible deficiencies of many protocols for differentiating MSCs into neurocytes.…”

Induction of unfolded protein response during neuronal induction of rat bone marrow stromal cells and mouse embryonic stem cells

“…To support the clinical potential of BMSC transplantation, many attempts to differentiate BMSCs in vitro into neural cells have been made. In this connection, a few results showing the molecular pathways and gene expression patterns specific for in vitro neuronal differentiation of mesenchymal stem cells have been published (Jori et al, 2005;Wang et al, 2007). However, precise mechanism for neuronal differentiation or functional role of BMSCs in the brain still remains to be determined.…”

Cerebrospinal Fluid following Cerebral Ischemia Accelerates the Proliferation of Bone Marrow Stromal Cells in vitro

“…[24,25] Jaiswal et al [26] reported a potential mechanism involving MAP-kinase activation in the osteogenic differentiation of adult stem cells and suggested that the commitment of hMSCs into osteogenic or adipogenic lineages is governed by the activation or inhibition of ErK. Jori et al [27] has also reported that MEK-ErK signaling could contribute to neural commitment and differentiation in vitro in marrow stromal stem cells. The absence of any effect of ErK activation in the present study could be because the culture duration in our study was too short for differentiation of the MSCs after the CSF treatment.…”