Daily bone marrow cell transplantations for the management of fast neurodegenerative processes

Abstract

Cell therapy has been proven to be a promising treatment for fighting neurodegenerative diseases. As neuronal replacement presents undeniable complications, the neuroprotection of live neurons arises as the most suitable therapeutic approach. Accordingly, the earlier the diagnosis and treatment, the better the prognosis. However, these diseases are commonly diagnosed when symptoms have already progressed towards an irreversible degenerative stage. This problem is especially dramatic when neurodegeneration is aggressive and rapidly progresses. One of the most interesting approaches for neuroprotection is the fusion between healthy bone marrow‐derived cells and neurons, as the former can provide the latter with regular/protective genes without harming brain parenchyma. So far, this phenomenon has only been identified in Purkinje cells, whose death is the cause of different diseases like cerebellar ataxias. Here we have employed a model of aggressive cerebellar neurodegeneration, the Purkinje Cell Degeneration mouse, to optimize a cell therapy based on bone marrow‐derived cell and cell fusion. Our findings show that the substitution of bone marrow in diseased animals by healthy bone marrow, even prior to the onset of neurodegeneration, is not fast enough to stop neuronal loss in time. Conversely, avoiding bone marrow replacement and ensuring a regular supply of healthy cells through continuous, daily transplants, the neurodegenerative milieu of PCD is enough to attract those transplanted elements. Furthermore, in the most affected cerebellar regions, more than a half of surviving neurons undergo a process of cell fusion. Therefore, this method deserves consideration as a means to impede neuronal cell death.

Donor Bone Marrow Derived Macrophage Engraftment into the Central Nervous System of Allogeneic Transplant Patients

“…Since donor cell engraftment maybe limited by the low numbers of circulating donor precursor cells (monocytes) in the early post-transplant period, repeat stem cell transplants could increase the number of donor cells in the CNS. 32 Consistently, we observed that patients with 2 or more transplants showed higher levels of donor cell engraftment than those with a single transplant, averaging 16.3% (12.2-25.1%) of microglial cells (Figure 4A; Table 1 B16-B19) Preclinical studies have reported that engrafted BMDM are long-lived and capable of self-replication with clonal donor cell numbers increasing over time following transplant. 25,33 Our data agree with these reports.…”

Transplanted Human Neural Progenitor Cells Attenuate Motor Dysfunction and Lengthen Longevity in a Rat Model of Ataxia

“…The researchers believe that this and not any changes within the central nervous system were the cause of the improvements in the PCD model 39 . Later work by the same group has found that daily treatment with health bone marrow cells starting before neurodegeneration in the PCD mice was successful in ameliorating the neural damage found in PCD mice 40 . These results show the difficulty of cell transplantation using any type of cell line, but also the effectiveness of non-neural cell-based treatments for treatment of neurodegeneration.…”

“…Furthermore, the NPCs have not been the only cell type used for transplantation studies with ataxia models. Extensive work has been done on the PCD mouse model 39 , 40 . The PCD mouse shows similar motor dysfunctions and various cell death, including that of Purkinje cells.…”

Oleoylethanolamide Delays the Dysfunction and Death of Purkinje Cells and Ameliorates Behavioral Defects in a Mouse Model of Cerebellar Neurodegeneration

“…In addition, it should be noted that motor impairments in PCD mice at this age could be responsible for the results obtained in the memory and the social preference tests at P40; therefore, no conclusive results can be drawn. Regardless of this, it is important to note that we managed to delay the degeneration in PCD mice and increase the temporal window in which other therapeutic approaches could be employed synergistically to fight against rapid and aggressive neurodegeneration [58,66,67].…”