Stem cell-based strategies are of particular interest in the study of neurological diseases because mature brains have a limited capacity for self-repair. MSCs have great potential to serve as therapeutic agents for stroke treatment, because they are easily obtained and can be expanded rapidly ex vivo for transplantation [9, 10]. Transplanted MSCs in an ischemic region of the rat brain can differentiate into neural cells and promote functional improvement [11, 12]. Furthermore, MSCs can improve neurological deficits in stroke patients . hUCB-MSCs have proven to be more advantageous than bone marrow-derived MSCs in terms of cell procurement, storage, and transplantation . Moreover, the number and differentiation ability of bone marrow-derived MSCs significantly decrease with age . Thus, hUCB-MSCs are a better candidate for clinical applications of stem cell-based therapies.
In this study, we confirmed that intravenous infusion of hUCB-MSCs after transient MCAO in rabbits reduced the infarction volume, prevented ischemic neuronal damage, and improved neurological deficits. These results are consistent with previous studies in which beneficial effects were observed in cerebral ischemic models infused with MSCs [16–18].
1H-MRS enables serial, non-invasive monitoring of neuronal metabolite disturbances in the diseased brain in vivo, such as Cho, Cr, NAA, and Lac . NAA is located primarily in neuroaxonal tissues. Its presence can be used to determine neuron numbers and activity. Therefore, decreased NAA indicates impaired neuronal and/or axonal function . Cho is a marker of cell reversal and reflects the stability of cell membranes. Its peak level is usually related to cell membrane synthesis and catabolism, which depends on the concentrations of Cho in membrane phospholipids. Cho peaks can reflect the amount of Cho-containing compounds in the myelin membrane, such as phosphocholine and glycerophosphocholine. Abnormal Cho peaks can be observed in pathological conditions such as demyelination, degenerative changes, and ischemic states . Lac is a redox partner of pyruvate and metabolic intermediate between glycolysis and Kreb’s or the tricarboxylic acid (TCA) cycle. When oxygen availability is low because of perfusion deficiency or other metabolic stress, the rate of the TCA cycle decreases and pyruvate produced by glycolysis accumulates and is converted to Lac. Thus, Lac can serve as a marker of anaerobic metabolism in stroke. Lac detection by 1H-MRS in vivo may allow identification of regions of metabolic stress in the brain and other human tissues, which can potentially identify regional ischemia in stroke . Therefore, serial decreases in NAA/Cr and Cho/Cr ratios and elevations in the Lac/Cr ratio essentially indicate brain damage. In our current study, we observed an elevated Lac/Cr ratio and a marked decrease in NAA/Cr and Cho/Cr ratios at 24 h after MCAO in the MCAO group (p < 0.01), which was consistent with previous studies [18, 21]. However, after intravenous delivery of hUCB-MSCs, 1H-MRS analysis at 24 h and 2 weeks indicated a significant decrease in the Lac/Cr ratio and a marked elevation in NAA/Cr and Cho/Cr ratios compared with those in MCAO and saline groups. These findings suggest neuroprotection induced by the transplantation procedure.
MSCs produce an impressive array of neuroprotective compounds. In a meta-analysis of 60 preclinical studies of intravenously delivered stem cells, Janowski and colleagues reported that good patient outcomes were correlated with inhibition of apoptosis . Neuroprotection by the transplantation procedure may be direct via secretion of neuroprotective compounds or indirect via immunomodulation, angiogenesis, or amplification of the endogenous neural stem cell response . In our present study, hUCB-MSC transplantation restored the 1H-MRS data to near normal at 2 weeks after MCAO. Moreover, hUCB-MSC transplantation protected neurons in the infarct area. Thus, our data may offer additional supportive evidence for neuroprotection by stem cells.
The safety of stem cell transplantation for treating ischemia is important. Short-term concerns include acute infusional toxicities to important organs, such as hepatotoxicity and renal toxicity. Long-term concerns include the risk of tumor formation . In our present study, no influence was found on CBCs, liver function, renal function, serum glucose, or serum lipids in MCAO rabbits at 24 h and 2 weeks after transplantation.