Human umbilical cord blood-derived mesenchymal stem cells improve neuropathology and cognitive impairment in an Alzheimer's disease mouse model through modulation of neuroinflammation

Lee, Hyun Ju; Lee, Jong Kil; Lee, Hyun; Carter, Janet E.; Chang, Jong Wook; Oh, Wonil; Yang, Yoon Sun; Suh, Jun-Gyo; Lee, Byoung-Hee; Jin, Hee Kyung; Bae, Jae‐sung

doi:10.1016/j.neurobiolaging.2010.03.024

Cited by 241 publications

(182 citation statements)

References 56 publications

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“…Several studies have described the in vitro differentiation of MSCs into cells of the neuronal and glial lineage (3,88), but this occurs only when MSCs are cultured under particular experimental conditions as discussed above. The neuroprotective effects of MSC and CM treatments found in our study correlate with previous reports in animal models of CNS disorders (37,39), in which MSCs prevented axonal damage and promoted nerve fiber regeneration through the production of trophic factors.…”

Section: Discussionsupporting

confidence: 91%

Mesenchymal stem cells and conditioned medium avert enteric neuropathy and colon dysfunction in guinea pig TNBS-induced colitis

Robinson

Sakkal

Park

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Robinson AM, Sakkal S, Park A, Jovanovska V, Payne N, Carbone SE, Miller S, Bornstein JC, Bernard C, Boyd R, Nurgali K. Mesenchymal stem cells and conditioned medium avert enteric neuropathy and colon dysfunction in guinea pig TNBS-induced colitis. Am J Physiol Gastrointest Liver Physiol 307: G1115-G1129, 2014. First published October 9, 2014 doi:10.1152/ajpgi.00174.2014.-Damage to the enteric nervous system (ENS) associated with intestinal inflammation may underlie persistent alterations to gut functions, suggesting that enteric neurons are viable targets for novel therapies. Mesenchymal stem cells (MSCs) offer therapeutic benefits for attenuation of neurodegenerative diseases by homing to areas of inflammation and exhibiting neuroprotective, anti-inflammatory, and immunomodulatory properties. In culture, MSCs release soluble bioactive factors promoting neuronal survival and suppressing inflammation suggesting that MSC-conditioned medium (CM) provides essential factors to repair damaged tissues. We investigated whether MSC and CM treatments administered by enema attenuate 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced enteric neuropathy and motility dysfunction in the guinea pig colon. Guinea pigs were randomly assigned to experimental groups and received a single application of TNBS (30 mg/kg) followed by 1 ϫ 10 6 human bone marrow-derived MSCs, 300 l CM, or 300 l unconditioned medium 3 h later. After 7 days, the effect of these treatments on enteric neurons was assessed by histological, immunohistochemical, and motility analyses. MSC and CM treatments prevented inflammation-associated weight loss and gross morphological damage in the colon; decreased the quantity of immune infiltrate in the colonic wall (P Ͻ 0.01) and at the level of the myenteric ganglia (P Ͻ 0.001); prevented loss of myenteric neurons (P Ͻ 0.05) and damage to nerve processes, changes in ChAT, and nNOS immunoreactivity (P Ͻ 0.05); and alleviated inflammationinduced colonic dysmotility (contraction speed; P Ͻ 0.001, contractions/min; P Ͻ 0.05). These results provide strong evidence that both MSC and CM treatments can effectively prevent damage to the ENS and alleviate gut dysfunction caused by TNBS-induced colitis.

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Section: Discussionsupporting

confidence: 91%

Mesenchymal stem cells and conditioned medium avert enteric neuropathy and colon dysfunction in guinea pig TNBS-induced colitis

Robinson

Sakkal

Park

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…These findings are consistent with our recent findings in a transgenic mouse model of AD that soluble intercellular adhesion molecule-1 and galectin-3/decorin/progranulin, which are released from human umbilical cord blood mesenchymal stem cells (hUCB-MSCs), act in amyloid removal and as antiapoptotic effectors, respectively [11][12][13]. In addition, we found that transplantation of hUCB-MSCs improved memory deficits in an AD mouse model [14,15], although the underlying molecular mechanisms remain unclear.…”

supporting

confidence: 92%

GDF-15 Secreted from Human Umbilical Cord Blood Mesenchymal Stem Cells Delivered Through the Cerebrospinal Fluid Promotes Hippocampal Neurogenesis and Synaptic Activity in an Alzheimer's Disease Model

Kim

Lee

Chang

et al. 2015

Stem Cells and Development

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100

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Our previous studies demonstrated that transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) into the hippocampus of a transgenic mouse model of Alzheimer's disease (AD) reduced amyloid-b (Ab) plaques and enhanced cognitive function through paracrine action. Due to the limited life span of hUCB-MSCs after their transplantation, the extension of hUCB-MSC efficacy was essential for AD treatment. In this study, we show that repeated cisterna magna injections of hUCB-MSCs activated endogenous hippocampal neurogenesis and significantly reduced Ab42 levels. To identify the paracrine factors released from the hUCB-MSCs that stimulated endogenous hippocampal neurogenesis in the dentate gyrus, we cocultured adult mouse neural stem cells (NSCs) with hUCB-MSCs and analyzed the cocultured media with cytokine arrays. Growth differentiation factor-15 (GDF-15) levels were significantly increased in the media. GDF-15 suppression in hUCB-MSCs with GDF-15 small interfering RNA reduced the proliferation of NSCs in cocultures. Conversely, recombinant GDF-15 treatment in both in vitro and in vivo enhanced hippocampal NSC proliferation and neuronal differentiation. Repeated administration of hUBC-MSCs markedly promoted the expression of synaptic vesicle markers, including synaptophysin, which are downregulated in patients with AD. In addition, in vitro synaptic activity through GDF-15 was promoted. Taken together, these results indicated that repeated cisterna magna administration of hUCB-MSCs enhanced endogenous adult hippocampal neurogenesis and synaptic activity through a paracrine factor of GDF-15, suggesting a possible role of hUCB-MSCs in future treatment strategies for AD.

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“…58 Mesenchymal stromal cells, isolated from placenta or cord tissue, show promise for treatment of patients with brain injuries, degenerative brain diseases, peripheral vascular disease and spinal cord injury. 59 If UCBT proves successful as regenerative medicine therapy for common degenerative diseases, the numbers of UCBT may rise steeply; in addition, there may be momentum to bank UCB privately, so as to be available for personal use. As it is highly unlikely that every patient needing this type of therapy could have their own UCB stored, safe methods to use the hundreds of thousands of publically banked, fully qualified and HLA-typed, allogeneic UCB units in regenerative medicine should be developed.…”

Section: Regenerative Medicinementioning

confidence: 99%

Umbilical cord blood donation: public or private?

Ballen

Verter²,

Kurtzberg

2015

Bone Marrow Transplant

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Umbilical cord blood (UCB) is a graft source for patients with malignant or genetic diseases who can be cured by allogeneic hematopoietic cell transplantation (HCT), but who do not have an appropriately HLA-matched family or volunteer unrelated adult donor. Starting in the 1990s, unrelated UCB banks were established, accepting donations from term deliveries and storing UCB units for public use. An estimated 730 000 UCB units have been donated and stored to date and ∼ 35 000 UCB transplants have been performed worldwide. Over the past 20 years, private and family banks have grown rapidly, storing ∼ 4 million UCB units for a particular patient or family, usually charging an up-front and yearly storage fee; therefore, these banks are able to be financially sustainable without releasing UCB units. Private banks are not obligated to fulfill the same regulatory requirements of the public banks. The public banks have released ∼ 30 times more UCB units for therapy. Some countries have transitioned to an integrated banking model, a hybrid of public and family banking. Today, pregnant women, their families, obstetrical providers and pediatricians are faced with multiple choices about the disposition of their newborn's cord blood. In this commentary, we review the progress of UCB banking technology; we also analyze the current data on pediatric and adult unrelated UCB, including the recent expansion of interest in transplantation for hemoglobinopathies, and discuss emerging studies on the use of autologous UCB for neurologic diseases and regenerative medicine. We will review worldwide approaches to UCB banking, ethical considerations, criteria for public and family banking, integrated banking ideas and future strategies for UCB banking.

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Human umbilical cord blood-derived mesenchymal stem cells improve neuropathology and cognitive impairment in an Alzheimer's disease mouse model through modulation of neuroinflammation

Cited by 241 publications

References 56 publications

Mesenchymal stem cells and conditioned medium avert enteric neuropathy and colon dysfunction in guinea pig TNBS-induced colitis

Mesenchymal stem cells and conditioned medium avert enteric neuropathy and colon dysfunction in guinea pig TNBS-induced colitis

GDF-15 Secreted from Human Umbilical Cord Blood Mesenchymal Stem Cells Delivered Through the Cerebrospinal Fluid Promotes Hippocampal Neurogenesis and Synaptic Activity in an Alzheimer's Disease Model

Umbilical cord blood donation: public or private?

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