Secretion of angiogenic proteins by human multipotent mesenchymal stromal cells and their clinical potential in the treatment of avascular osteonecrosis

Abstract

Osteonecrosis is a frequent complication after treatment for childhood leukemia and other steroid-based therapies. The success rate of core decompression surgery is limited. Therefore, we evaluated relevant biological characteristics of human multipotent mesenchymal stromal cells (MSCs) in vitro. MSCs cultured under low-oxygen tensions showed decreased proliferation and differentiation into bone. However, these MSCs secreted significant amounts of vascular endothelial-derived factor in the presence of interferon-c. These in vitro results with potential effects on neovascularization and bone regeneration as well as findings in animal models prompted us to treat five patients with steroid-induced osteonecrosis of the femur by core decompression surgery and instillation of expanded autologous MSCs. Within 3 weeks of culture, sufficient numbers of MSCs were generated using animal protein-free culture conditions. No chromosomal aberrations were detected by matrix-based comparative genomic hybridization. Application of MSCs during core decompression was feasible and safe. Median follow-up is 16 months and the patients in this pilot study reported clinical improvement. Formation of mineralized bone in the osteonecrotic cavity was proven by computed tomography. Taken together, MSCs display biological properties that may add to the efficiency of surgical treatment in osteonecrosis and should be evaluated in larger patient cohorts.

Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase

“…28,29 Of particular interest, very promising data from a pilot study on the clinical use of MSCs in the treatment of steroid-induced avascular osteonecrosis have recently reported in this journal. 30 Antiprotozoal and antiviral effector functions of MSCs, however, appear more relevant in the setting of allogeneic hematopoietic stem cell transplantation where severe infections with herpesviruses and intracellular parasites such as Toxoplasma gondii have a prominent role. 31 This is particularly noteworthy as MSCs are preferentially utilized in those patients suffering from GvHD who have failed several lines of pharmacological immunosuppressive therapy and therefore are severely immunodeficient.…”

Risk factors for symptomatic osteonecrosis in childhood ALL: A retrospective study of a Slovenian pediatric ALL population between 1970 and 2004

“…Thus, any additional factors decreasing MSC number or differentiation into osteoblasts may worsen the osteonecrotic process, induced by GC. This could explain why only a small fraction of patients receiving GC therapy develop ON and why a relatively small percentage of patients with positive radiograph and MRI osteonecrotic results are symptomatic (35). In the case of 6-MP therapy of the present study, decreased TPMT activity leads to greater bone marrow toxicity and decreased MSC number, which may impair bone formation and repair the forming osteonecrotic lesion.…”

“…MSCs, cultured in the low-oxygen conditions, resembling those in the osteonecrotic lesion, were found to produce high levels of vasculogenic cytokines (35). Since vascular damage is speculated to be one of the primary ON causes, this induction of the vascularization by MSCs may lead to ON improvement (35). Thus, any additional factors decreasing MSC number or differentiation into osteoblasts may worsen the osteonecrotic process, induced by GC.…”

“…Recently it has also been implicated that MSCs may have an important role in the repair process of osteonecrotic lesion (35). MSCs, cultured in the low-oxygen conditions, resembling those in the osteonecrotic lesion, were found to produce high levels of vasculogenic cytokines (35). Since vascular damage is speculated to be one of the primary ON causes, this induction of the vascularization by MSCs may lead to ON improvement (35).…”

“…In this manner, 6-MP could aggravate the effects of GC on MSCs, which include the reduction of MSC number in bone marrow (33) and increased differentiation of MSCs into adipocytes at the expense of osteogenesis (34). Recently it has also been implicated that MSCs may have an important role in the repair process of osteonecrotic lesion (35). MSCs, cultured in the low-oxygen conditions, resembling those in the osteonecrotic lesion, were found to produce high levels of vasculogenic cytokines (35).…”