Transplantation of Endothelial Progenitor Cells into the Lung to Alleviate Pulmonary Hypertension in Dogs

Takahashi, Mitsuru; Nakamura, Tatsuo; Toba, Toshinari; Kajiwara, Naohiro; Kato, Harubumi; Shimizu, Yasuhiko

doi:10.1089/1076327041348563

Cited by 120 publications

(88 citation statements)

References 19 publications

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“…Chord blood-derived human EPCs overexpressing adrenomedullin markedly reduced pulmonary vascular resistance and improved survival rates after intravenous administration into nude rats with monocrotalineinduced pulmonary hypertension compared with control animals treated with either saline or EPCs alone. 95 Similarly, intraparenchymal injection of autologous EPCs in dogs with pulmonary hypertension brought about significant improvements in mean pulmonary artery pressure, cardiac output, and pulmonary vascular resistance 96 …”

Section: Epc Cell Therapy For Pulmonary Hypertensionmentioning

confidence: 99%

Therapeutic Potential of Endothelial Progenitor Cells in Cardiovascular Diseases

et al. 2005

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Abstract-Endothelial dysfunction and cell loss are prominent features in cardiovascular disease. Endothelial progenitor cells (EPCs) originating from the bone marrow play a significant role in neovascularization of ischemic tissues and in re-endothelialization of injured blood vessels. Several studies have shown the therapeutic potential of EPC transplantation in rescue of tissue ischemia and in repair of blood vessels and bioengineering of prosthetic grafts. Recent small-scale trials have provided preliminary evidence of feasibility, safety, and efficacy in patients with myocardial and critical limb ischemia. However, several studies have shown that age and cardiovascular disease risk factors reduce the availability of circulating EPCs (CEPCs) and impair their function to varying degrees. In addition, the relative scarcity of CEPCs limits the ability to expand these cells in sufficient numbers for some therapeutic applications. Priority must be given to the development of strategies to enhance the number and improve the function of CEPCs. Furthermore, alternative sources of EPC such as chord blood need to be explored. Strategies for improvement of cell adhesion, survival, and prevention of cell senescence are also essential to ensure therapeutic viability. Genetic engineering of EPCs may be a useful approach to developing these cells into efficient therapeutic tools. In the clinical arena there is pressing need to standardize the protocols for isolation, culture, and therapeutic application of EPC. Large-scale multi-center randomized trials are required to evaluate the long-term safety and efficacy of EPC therapy. Despite these hurdles, the outlook for EPC-based therapy for cardiovascular disease is promising. (Hypertension. 2005;46:7-18.)

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Section: Epc Cell Therapy For Pulmonary Hypertensionmentioning

confidence: 99%

Therapeutic Potential of Endothelial Progenitor Cells in Cardiovascular Diseases

et al. 2005

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“…The field is complicated by the controversy over how to identify circulating progenitors and what exactly their contribution is to angiogenesis. Despite this controversy ex vivo-expanded endothelial-like progenitor cells have shown therapeutic benefit in short-term studies in animal models of PAH (6,7) and in a randomized controlled trial in humans with idiopathic PAH (8). Although enthusiasm for the therapeutic use of these cells in PAH is gaining momentum, there is little work detailing the function of endogenous human EPCs in PAH pathophysiology.…”

mentioning

confidence: 99%

Evidence of Dysfunction of Endothelial Progenitors in Pulmonary Arterial Hypertension

Toshner¹,

Voswinckel²,

Southwood³

et al. 2009

Am J Respir Crit Care Med

214

234

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Rationale: Severe pulmonary arterial hypertension (PAH) is characterized by the formation of plexiform lesions and concentric intimal fibrosis in small pulmonary arteries. The origin of cells contributing to these vascular lesions is uncertain. Endogenous endothelial progenitor cells are potential contributors to this process. Objectives: To determine whether progenitors are involved in the pathobiology of PAH. Methods: We performed immunohistochemistry to determine the expression of progenitor cell markers (CD133 and c-Kit) and the major homing signal pathway stromal cell-derived factor-1 and its chemokine receptor (CXCR4) in lung tissue from patients with idiopathic PAH, familial PAH, and PAH associated with congenital heart disease. Two separate flow cytometric methods were employed to determine peripheral blood circulating numbers of angiogenic progenitors. Late-outgrowth progenitor cells were expanded ex vivo from the peripheral blood of patients with mutations in the gene encoding bone morphogenetic protein receptor type II (BMPRII), and functional assays of migration, proliferation, and angiogenesis were undertaken. Measurements and Main Results: There was a striking up-regulation of progenitor cell markers in remodeled arteries from all patients with PAH, specifically in plexiform lesions. These lesions also displayed increased stromal cell-derived factor-1 expression. Circulating angiogenic progenitor numbers in patients with PAH were increased compared with control subjects and functional studies of lateoutgrowth progenitor cells from patients with PAH with BMPRII mutations revealed a hyperproliferative phenotype with impaired ability to form vascular networks. Conclusions: These findings provide evidence of the involvement of progenitor cells in the vascular remodeling associated with PAH. Dysfunction of circulating progenitors in PAH may contribute to this process. Keywords: pulmonary hypertension; endothelial progenitorSevere pulmonary arterial hypertension (PAH) is a rare but devastating condition with a poor prognosis. The conventional model of pulmonary endothelial dysfunction in PAH includes endothelial cell damage, failure of repair, and compromise of barrier integrity (1). Two types of vascular lesions predominate in small pulmonary arteries: concentric intimal lesions consisting of myofibroblast proliferation and smooth muscle hypertrophy with resultant luminal narrowing, and plexiform lesions characterized by disorganized focal proliferation of endothelial channels (2). The vascular injury has been hypothesized to lead to the emergence of apoptosis-resistant endothelial cell clones, and Lee and coworkers (3) have suggested that plexiform lesions, at least in the idiopathic form of PAH, are monoclonal in origin. The appearance of plexiform lesions is thought to signify a poor prognosis (4), but little is understood about the evolution of these focal areas of neoangiogenesis. Their contribution to increased vascular resistance is unclear, although three-dimensional reconstruction studies sugge...

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“…Histological evaluation revealed both improvement in the medial thickness of the small pulmonary artery and neovascularization of the lung tissue. These results indicate that EPC transplantation into the lung is effective at preventing the progression of dehydromonocrotaline-induced pulmonary hypertensive in dogs, and suggest a new therapeutic option for PPH [22].…”

Section: Discussionmentioning

confidence: 63%

Neo-Revascularization as the Potential Treatment for Patient Suffering from Pulmonary Arterial Hypertension (Myth or Reality)

Lacis¹

2013

CMR

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Pulmonary arterial hypertension (APAH, IPAH) is a devastating, progressive disease with increasingly debilitating symptoms [1,2].Intrapulmonary delivery of autologous stem cells could be beneficial for pathogenetic treatment for patients with severe pulmonary arterial hypertension.Two patients with severe pulmonary artery hypertension received intrapulmonary autologous mesenchymal (mononuclear) stem cell transplantation and stem cell transplantation in pulmonary arteries. Patients were examined by scintigraphy of lungs during the periods 12, 14 and 27 months after stem cell transplantation. We find out that perfusion in all lung segments were improved after 14 and 27 months.

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Transplantation of Endothelial Progenitor Cells into the Lung to Alleviate Pulmonary Hypertension in Dogs

Cited by 120 publications

References 19 publications

Therapeutic Potential of Endothelial Progenitor Cells in Cardiovascular Diseases

Therapeutic Potential of Endothelial Progenitor Cells in Cardiovascular Diseases

Evidence of Dysfunction of Endothelial Progenitors in Pulmonary Arterial Hypertension

Neo-Revascularization as the Potential Treatment for Patient Suffering from Pulmonary Arterial Hypertension (Myth or Reality)

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