Bone marrow rejuvenation: an excellent potential therapy for age-related endothelial dysfunction

Introduction

Aging has been defined as “the sum of primary restrictions in regenerative mechanisms of multicellular organisms”.¹ In other words, aging can also be described as a progressive functional decline; a gradual degeneration of physiological function; or the intrinsic, inevitable and irreversible time-related process of loss of viability and increase in disease vulnerability.² As life expectancy rises, it has led to the rapid aging of populations. Aging is the key risk factor for major human chronic pathologies and has become a worldwide medical and social problem.

The most common diseases of aging include Alzheimer's, arthritis, cancer, diabetes, depression and cardiovascular disorders. Certainly, increasing age is also an independent risk factor for the development of atherosclerosis and coronary artery disease.^{3, 4} Aging is accompanied by endothelial cell senescence and the progressive decline of endothelial function.⁵ Endothelial dysfunction primarily contributes to impeded re-endothelialization and exacerbated neointima formation upon vascular pathological lesions. Thus, recovery from the decline of endothelial function helps to prevent age-related vascular disease. With increasing age and persistent reactive oxygen species production, the capacity of adjacent endothelial cells to repair endothelial injuries is limited, and vascular recovery becomes dependent on the incorporation of circulating endothelial progenitor cells (EPCs).⁶ Bone marrow-derived circulating EPCs play a significant role in vascular re-endothelialization and suppression of neointima formation after vascular injury.⁷ These cells can be mobilized under the modulation of vascular endothelial growth factor (VEGF), matrix metallopeptidase-9 (MMP-9) and other factors to participate in repair of endothelial injury. Aging impairs EPC mobilization, migration and homing to sites of vascular injury (Fig. 1).

Figure 1.

Age-related effects that impair the biological function of endothelial progenitor cells.

Bone marrow rejuvenation accelerates re-endothelialization by improving the biological function of EPCs

Improving EPC mobilization, migration capacity and endothelial function in the elderly is an excellent strategy against aged-related vascular injury. Bone marrow is the major source for adult stem and progenitor cells, including EPCs. Bone marrow rejuvenation may provide an excellent therapy by using EPCs to recover endothelial function and prevent age-related vascular injury. Fortunately, with great interest, we have read the recent article by Dr. Wang et al. demonstrating that bone marrow rejuvenation, accomplished by transplanting bone marrow from young mice to old mice, can stimulate re-endothelialization and alleviate neointima formation after vascular injury in aged mice.⁸

In their study, bone rejuvenation was achieved by transplanting bone marrow from eGFP transgenic mice to wild-type recipient mice. At eight weeks after transplantation, the mice were subjected to femoral artery wire injury to mimic endothelial injury. It was found that substantial levels of intimal hyperplasia (IH) developed after wire-induced vascular injury. However, bone marrow rejuvenation, the treatment of old mice with bone marrow from young mice (YTO group), significantly attenuated the severity of IH compared to old mice without bone marrow transplantation. Bone marrow rejuvenation also increased the rate of re-endothelialization. The number of eGFP⁺CD31⁺ EPCs was greatest in the YTO group, indicating that the eGFP⁺ EPCs, which were derived from bone marrow donors, were involved in and accelerated re-endothelialization.

To investigate how bone marrow rejuvenation can alleviate IH and accelerate the rate of re-endothelialization, the authors measured EPC migratory and adhesion capacities in vitro and mobilization function in response to vascular injury in vivo. The migratory ability of bone marrow EPCs in response to VEGF stimulation in the YTO group was better than that of the aged group. Similarly, bone marrow rejuvenation (YTO group) significantly increased the adhesion capacity of EPCs compared to the aged group. The number of circulating EPCs in the YTO group was significantly greater compared to the aged group in response to stimulation by vascular injury. These results indicated that many EPCs were mobilized from bone marrow after aged mice underwent bone marrow rejuvenation. It has been reported that the PI3K/Akt pathway plays a pivotal role in the mobilization, migration and homing functions of EPCs.⁹ The authors analyzed PI3K, Akt, FAK, etc., potential signals mediating VEGF-associated EPC migration. The data showed that PI3K, Akt and FAK were involved in EPC migration, and inhibitors of PI3K, Akt or FAK signaling partially attenuated EPC migration. In short, the entire study by Wang et al. could be summarized in Fig. 2.

Figure 2.

The entire research strategy and results of the study by Dr. Wang. *The authors investigated serum VEGF levels in different groups. It was found that young mice released higher levels of VEGF 24 hours after arterial injury. Certainly, it would be ideal if the authors could demonstrate increased serum VEGF in YTO mice.

The prospects and challenges of bone marrow rejuvenation for curing age-related endothelial dysfunction in the clinic

Typically, bone marrow transplantation is performed in the fields of hematology, oncology, metabolic disease and autoimmune disease, particularly for patients with certain hematological malignancies, such as multiple myeloma or leukemia. Bone marrow contains multiple stem and progenitor cell types, including hematopoietic stem cells, mesenchymal stem cells, EPCs and very small embryonic-like cells. These cells can be mobilized at varying degrees into the peripheral circulation upon a given stimulation. ¹⁰ Therefore, bone marrow transplantation is considered for the treatment of a variety of other diseases. Bone marrow rejuvenation reduced ischemic brain injury in aged rats ¹¹ and alleviated renal aging in old mice, ¹² aside from the treatment of age-related endothelial dysfunction. ¹³ Bone marrow transplantation seems as if the dawn of the night to refractory aging related endothelial dysfunction, but it still had to face many challenges for clinical application.

Allogeneic bone marrow transplantation between the elderly and the young is a difficult procedure to undergo. Human leukocyte antigen (HLA) matching between the donor and the recipient must be performed first. Therefore, effective matching of the donor to the recipient is extremely limited. Moreover, both donor and recipient must accept pretreatment, especially the recipient. Usually, the recipient receives high doses of chemotherapy and/or radiation to eliminate his own bone marrow and to suppress immune reactions prior to transplantation. It is an absolutely adventurous initiative to implement chemotherapy or radiation to weak elderly patients with vascular diseases, as these patients might not withstand the drastic pretreatment. Additionally, many inevitable complications could appear, including mucositis, veno-occlusive disease, severe infection, graft-versus-host disease, etc., both during and after the procedure. ¹⁴ All of these side effects would increase the mortality of elderly recipients, which has limited its use for treatment of age-related endothelial dysfunction.

We considered that autologous transplantation prior to allogeneic transplantation to treat age-related endothelial dysfunction. Autologous transplantation avoids HLA matching and reduces treatment-related mortality to a greater extent. If autologous transplantation is performed, one still must face another important issue, how to rejuvenate the bone marrow cells before transplantation. Modification of genes and miRNAs involved in EPC senescence might provide an excellent strategy to rejuvenate aged EPCs in vitro. ¹⁵ Only if the issue of EPC senescence was completely solved could autologous bone marrow transplantation be applied to age-related vascular disease.

Conclusion

In summary, many challenges remain regarding bone marrow transplantation for age-related vascular diseases in the clinic, but a bright future lies ahead. We firmly believe that this therapy will become a reality and will be widely used in the clinic in the near future as long as additional attention is given to it.