Systemic human CD34.sup.+ cells populate the brain and activate host mechanisms to counteract nigrostriatal degeneration

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From: Regenerative Medicine(Vol. 10, Issue 5)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 8,761 words
Lexile Measure: 1730L

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Author(s): Mando J Corenblum aff1 , Andrew J Flores aff1 aff2 , Michael Badowski aff3 , David T Harris aff3 , Lalitha Madhavan [*] aff1

Keywords:

6-OHDA; angiogenesis; CD34+ mononuclear cells; cord blood; neurogenesis; neuroprotection; Parkinson's disease

Stem cells have the unique ability to induce plasticity and repair in the nervous system [1-4 ]. In particular, the capacity of stem cells to prevail in challenging environments, such as those present during injury and disease, and activate cell survival and regeneration mechanisms in the recipient brain allows for the possibility of actually countering degenerative processes and inhibiting disease progression in chronic disorders such as Parkinson's disease (PD) [5-7 ]. More specifically, such a disease modifying ability of stem cells is especially relevant to PD given that a substantial number of dopamine (DA) neurons in the substantia nigra (SN) are still intact or only dysfunctional when PD is diagnosed - therefore suggesting that this population of surviving but imperiled DA neurons can be rescued from degeneration with timely intervention [8 ].

In this context, human umbilical cord blood has emerged as a valuable source of stem cells. Being readily available at birth, human cord blood cells (hCBCs) can be obtained relatively easily and ethically, compared with other cell types such as embryonic or neural stem cells [9-12 ]. Among the different cell types present in human cord blood, CD34 + mononuclear cells, which include hematopoietic stem and progenitor cells, show the ability to induce tissue protection and repair in models of neurodegeneration [9 ]. More specifically, these cells can induce regenerative and anti-inflammatory effects to promote cell survival and tissue homeostasis making them an attractive stem cell type to use in the context of early stages of DA neuron degeneration in PD [9,13-16 ].

In the current study, we investigated the ability of an enriched population of CD34+ cells to migrate into brain tissues upon peripheral administration, and prevent nigrostriatal degeneration in a 6-hydroxydopamine (6-OHDA) rat model of PD. More specifically, we postulated that CD34+ hCBCs, when given during the initial phases of 6-OHDA induced neurodegeneration, would be able to survive and stimulate protective mechanisms in the host brain to preserve the integrity of the nigrostriatal pathway. To this end, our analyses indicate that the systemic hCBCs can in fact infiltrate brain tissues and shield SN midbrain DA neurons and their terminals in the striatum from degeneration by activating multiple host-based defense mechanisms including neurogenesis, angiogenesis and reduced gliosis. Although systemic hCBC administration has been shown to induce protective and restorative effects in several neurological disease models, it has been difficult to localize surviving donor cells in the brain and gain a mechanistic understanding of how hCBCs may be mediating the observed therapeutic effects. The current study provides evidence that hCBCs can indeed survive in the host brain, and provides a dynamic model in which mechanisms underlying hCBC-mediated therapeutic effects can be further explored.

Methods

Isolation of human CD34+ cells

Cord blood samples were obtained, processed and cryopreserved within 24 h of...

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Gale Document Number: GALE|A424015187