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Keywords:

  • bone marrow-derived immature cells;
  • CD34-positive cells;
  • cell-based therapy;
  • microcirculation;
  • vascular dementia

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CIRCULATING BONE MARROW-DERIVED IMMATURE CELLS AND CARDIOVASCULAR DISEASES
  5. CIRCULATING BONE MARROW-DERIVED IMMATURE CELLS AND CEREBROVASCULAR DISEASES
  6. TRANSPLANTATION OF BONE MARROW-DERIVED IMMATURE CELLS AND RESTORATION OF IMPAIRED MICROCIRCULATION
  7. DISCUSSION: CELL BASED THERAPY FOR PATIENTS WITH VASCULAR DEMENTIA
  8. ACKNOWLEDGEMENTS
  9. REFERENCES

The homeostasis of neuronal cells is maintained by the cerebral circulation and blood–brain barrier. Circulating bone marrow-derived immature cells, including CD34-positive (CD34+) cells, have been implicated in homeostasis of the cerebral microvasculature. Decreased levels of circulating CD34+ cells, associated with ageing and/or cardiovascular risk factors, correlate with poor clinical outcomes in patients with cerebrovascular and cardiovascular diseases. Clinical trials with local transplantation of bone marrow-derived immature cells for patients with limb ischaemia, including Buerger's disease and arteriosclerosis obliterans, have been shown to improve impaired microcirculation. In the present review, current findings about the correlation between circulating immature cells and microcirculation are reviewed, and the possibility of novel cell-based therapy in patients with vascular dementia is discussed.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CIRCULATING BONE MARROW-DERIVED IMMATURE CELLS AND CARDIOVASCULAR DISEASES
  5. CIRCULATING BONE MARROW-DERIVED IMMATURE CELLS AND CEREBROVASCULAR DISEASES
  6. TRANSPLANTATION OF BONE MARROW-DERIVED IMMATURE CELLS AND RESTORATION OF IMPAIRED MICROCIRCULATION
  7. DISCUSSION: CELL BASED THERAPY FOR PATIENTS WITH VASCULAR DEMENTIA
  8. ACKNOWLEDGEMENTS
  9. REFERENCES

Homeostasis of the microcirculation involves a delicate balance between injurious and reparative processes. Recently, the important contribution of circulating bone marrow-derived immature cells, including CD34-positive cells (CD34+), has been recognized to play a role in the maintenance of the microvasculature, both as a source of endothelial cells1 and growth/angiogenesis factors.2 Based on these findings, many observational studies have been initiated to correlate the decreased level of circulating bone marrow-derived immature cells to impaired microcirculation, followed by basic experiments and clinical trials that support the therapeutic effect of bone marrow-derived immature cells on restoration of impaired microcirculation.

CIRCULATING BONE MARROW-DERIVED IMMATURE CELLS AND CARDIOVASCULAR DISEASES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CIRCULATING BONE MARROW-DERIVED IMMATURE CELLS AND CARDIOVASCULAR DISEASES
  5. CIRCULATING BONE MARROW-DERIVED IMMATURE CELLS AND CEREBROVASCULAR DISEASES
  6. TRANSPLANTATION OF BONE MARROW-DERIVED IMMATURE CELLS AND RESTORATION OF IMPAIRED MICROCIRCULATION
  7. DISCUSSION: CELL BASED THERAPY FOR PATIENTS WITH VASCULAR DEMENTIA
  8. ACKNOWLEDGEMENTS
  9. REFERENCES

Repair of the microvasculature has traditionally been characterized by the replacement of damaged cerebral endothelium from the outgrowth of pre-existing vessels. However, the contribution of circulating bone marrow-derived immature cells, including CD34+ cells, has been identified and assigned a role in the maintenance of the vasculature.1 The bone marrow-derived immature cells serve as a pool of endothelial progenitor cells and a source of growth/angiogenesis factors.2 Risk factors for cardiovascular disease have been shown to adversely affect the level of circulating bone marrow-derived immature cells3 and CD34+ cells.4 Decreased levels of bone marrow-derived circulating immature cells correlate with vascular dysfunction3 and poor cardiovascular outcomes.5–7

CIRCULATING BONE MARROW-DERIVED IMMATURE CELLS AND CEREBROVASCULAR DISEASES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CIRCULATING BONE MARROW-DERIVED IMMATURE CELLS AND CARDIOVASCULAR DISEASES
  5. CIRCULATING BONE MARROW-DERIVED IMMATURE CELLS AND CEREBROVASCULAR DISEASES
  6. TRANSPLANTATION OF BONE MARROW-DERIVED IMMATURE CELLS AND RESTORATION OF IMPAIRED MICROCIRCULATION
  7. DISCUSSION: CELL BASED THERAPY FOR PATIENTS WITH VASCULAR DEMENTIA
  8. ACKNOWLEDGEMENTS
  9. REFERENCES

To investigate the correlation between the level of circulating bone marrow-derived immature cells and cerebrovascular functions, we have evaluated the level of circulating CD34+ cells in patients with stroke. Similar to the findings observed in patients with cardiovascular disease, patients with cerebrovascular disease have decreased levels of circulating bone marrow-derived immature cells, the latter associated with impaired cerebrovascular function.4 In contrast, increased levels of bone marrow-derived immature cells are associated with neovascularization of the ischaemic brain, such as in patients with Moyamoya disease.8 Because cerebrovascular function is one of the most important elements for the maintenance of cognitive function, the level of circulating bone marrow-derived immature cells in patients with vascular dementia and Alzheimer's disease have been evaluated. The results showed a significant reduction of circulating CD34+ cells was observed in patients with vascular dementia, but no reduction was observed in patients with Alzheimer's disease.9 These results might reflect the aetiological difference between vascular dementia and Alzheimer's disease. The correlation between the level of cognitive function and CD34+ cells in patients with cerebral infarction was also evaluated, and it was found that a decrease of CD34+ cells is correlated with the severity of cognitive dysfunction.10 Furthermore, patients with lower levels of circulating CD34+ cells showed significant worsening of cognitive function in 1 year.11 These findings point to impaired reparative processes of the microcirculation associated with decreased levels of circulating CD34+ cells. In turn, the latter impacts negatively on maintenance of cognitive function. It has been proposed that the level of CD34+ cells is a distinct marker of cerebrovascular ‘health’ and the risk of progressive cognitive impairment in patients with dementia, including vascular dementia and Alzheimer's disease.9–11

TRANSPLANTATION OF BONE MARROW-DERIVED IMMATURE CELLS AND RESTORATION OF IMPAIRED MICROCIRCULATION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CIRCULATING BONE MARROW-DERIVED IMMATURE CELLS AND CARDIOVASCULAR DISEASES
  5. CIRCULATING BONE MARROW-DERIVED IMMATURE CELLS AND CEREBROVASCULAR DISEASES
  6. TRANSPLANTATION OF BONE MARROW-DERIVED IMMATURE CELLS AND RESTORATION OF IMPAIRED MICROCIRCULATION
  7. DISCUSSION: CELL BASED THERAPY FOR PATIENTS WITH VASCULAR DEMENTIA
  8. ACKNOWLEDGEMENTS
  9. REFERENCES

Based on the findings, a new strategy has been proposed for enhancing recovery from ischaemic stress by administration of bone marrow-derived immature cells to stimulate formation and restore microvasculature. Recent reports have shown that infusion of bone marrow-derived immature cells results in their incorporation into the neovasculature at the ischaemic site and limiting of tissue damage in animal models of myocardial ischaemia12 and limb ischaemia.13 Similar to these observations, it has been shown that administration of CD34-positive cells after stroke enhances neovascularization.14 Furthermore, neovascularization has been shown to be essential for the survival of injury-induced neuronal stem cells that results in acceleration of functional recovery at the chronic phase. These results are consistent with the finding that cerebrovascular function, maintained at least in part by circulating bone marrow-derived immature cells, is one of the main elements that support the brain function.

Based on these findings, clinical trials have been initiated in patients with limb ischaemia with promising results.15,16 These results clearly showed that bone marrow-derived immature cells restore impaired microcirculation in patients with chronic ischaemia. Similarly, clinical trials,17,18 including a double-blind placebo control trial,19 showed that bone marrow transplantation improves clinical outcomes in patients with myocardial infarction.

To apply these experimental and clinical findings to patients with cerebral ischaemia, the required minimum number of bone marrow-derived cells and therapeutic time window for cell therapy has been evaluated and its safety using large animals has been confirmed. Based on these observations, protocol for cell-based therapy in patients after stroke was prepared. In 2007, the protocol was approved by the institutional review board of the National Cerebral and Cardiovascular Center and the council of the Ministry of Health, Labour and Welfare (ClinicalTrials.gov Identifier: NCT01028794). The clinical trial is ongoing now and will be finished by 2011.

DISCUSSION: CELL BASED THERAPY FOR PATIENTS WITH VASCULAR DEMENTIA

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CIRCULATING BONE MARROW-DERIVED IMMATURE CELLS AND CARDIOVASCULAR DISEASES
  5. CIRCULATING BONE MARROW-DERIVED IMMATURE CELLS AND CEREBROVASCULAR DISEASES
  6. TRANSPLANTATION OF BONE MARROW-DERIVED IMMATURE CELLS AND RESTORATION OF IMPAIRED MICROCIRCULATION
  7. DISCUSSION: CELL BASED THERAPY FOR PATIENTS WITH VASCULAR DEMENTIA
  8. ACKNOWLEDGEMENTS
  9. REFERENCES

The level of circulating CD34+ cells in more than 2000 patients with their clinical background has been evaluated. It was found that the level of circulating CD34+ cells is relatively low in young people, especially females with no cardiovascular risk (Fig. 1). However, the level of CD34+ cells increase with age, especially in patients with cardiovascular risk, followed by a gradual decrease in number with the onset of vascular events. These results lead the authors to hypothesize that exhaustion of bone marrow cells in patients might be associated with microvascular dysfunction and vascular dementia.9,11 Consistent with these findings, it was shown that the rejuvenation of bone marrow from aged animals with cells from young animals enhances the response of microcirculation and reduces brain damage after induction of stroke followed by improved neurological functions.20 The relevance of these findings is emphasized by the availability of potential sources of ‘young bone marrow cells’ for future therapeutic use. In addition to cord blood and bone marrow-derived haematopoietic stem cells, the therapeutic potential of induced pluripotent stem cell-derived haematopoietic stem cells is being reported for various haematopoietic disorders. The present findings, taken together with recent progress in stem cell technologies, suggest the possible therapeutic potential of this approach is relevant to the treatment of a large number of conditions, including disorders of vascular dementia.

image

Figure 1. Correlation between the level of circulating CD34+ cells and ageing (schema). The level of circulating CD34+ cells is relatively low in young people. The level gradually increases with age, probably because of the mobilization from the bone marrow to repair damaged microvasculature. While circulating CD34+ cells can be maintained in high levels, no vascular event occurs. However, with exhaustion of bone marrow, the level of circulating CD34+ cells decreases, accompanied by multiple stroke events.

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REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CIRCULATING BONE MARROW-DERIVED IMMATURE CELLS AND CARDIOVASCULAR DISEASES
  5. CIRCULATING BONE MARROW-DERIVED IMMATURE CELLS AND CEREBROVASCULAR DISEASES
  6. TRANSPLANTATION OF BONE MARROW-DERIVED IMMATURE CELLS AND RESTORATION OF IMPAIRED MICROCIRCULATION
  7. DISCUSSION: CELL BASED THERAPY FOR PATIENTS WITH VASCULAR DEMENTIA
  8. ACKNOWLEDGEMENTS
  9. REFERENCES
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