Reversing bone loss by directing mesenchymal stem cells to bone

Abstract

Bone regeneration by systemic transplantation of mesenchymal stem cells (MSCs) is problematic due to the inability to control the MSCs’ commitment, growth and differentiation into functional osteoblasts on the bone surface. Our research group has developed a method to direct the MSCs to the bone surface by conjugating a synthetic peptidomimetic ligand (LLP2A) that has high affinity for activated α4β1 integrin on the MSC surface, with a bisphosphonates (alendronate) that has high affinity for bone (LLP2A-Ale), to direct the transplanted MSCs to bone. Our in vitro experiments demonstrated that mobilization of LLP2A-Ale to hydroxyapatite accelerated MSC migration that was associated with an increase in the phosphorylation of Akt kinase and osteoblastogenesis. LLP2A-Ale increased the homing of the transplanted MSCs to bone as well as the osteoblast surface, significantly increased the rate of bone formation and restored both trabecular and cortical bone loss induced by estrogen deficiency or advanced age in mice. These results support LLP2A-Ale as a novel therapeutic option to direct the transplanted MSCs to bone for the treatment of established bone loss related to hormone deficiency and aging.

Inhibition of FAAH confers increased stem cell migration via PPARα

“…In this context, a recent study from our group found the nonpsychoactive phytocannabinoid, cannabidiol, to enhance the migratory potential of human mesenchymal stem cells (MSCs) ( 33 ). It is noteworthy that the pluripotent MSCs contribute to healing processes of injured tissues such as myocardium ( 34,35 ), injured spots of the eye ( 36 ), and bone tissue ( 37,38 ). Thus endocannabinoids and endocannabinoid-like substances, as well as enzymes that degrade these substances, are discussed as an endogenous system that regulates the differentiation of neural tissue (39)(40)(41), modulates embryogenesis ( 42 ), and coordinates remodeling of bone tissue ( 43 ).…”

Runx2/Osterix and Zinc Uptake Synergize to Orchestrate Osteogenic Differentiation and Citrate Containing Bone Apatite Formation

“…Osteoblastogenesis precedes propagation of mineral onto an extracellular matrix (ECM) consisted of collagen fibrils, osteocalcin, and osteopontin (OPN) secreted by the differentiating MSCs 2. Nanocrystal nucleation of apatite subsequently forms on such mineralized ECM.…”

Editorial: 2013—A Year of Clinical Success and Great Scientific Innovation in the Stem Cell Field

“…Manuscripts covered many advances in understanding the fundamental mechanisms that control stem and progenitor cell fate, and advances in working toward treating all tissues, from the lower extremities to the brain. Exciting basic and translational research was reported in using stem cells to treat osteoporosis [11], spinal cord injuries [12,13], radiation-induced fibrosis [14], glaucoma [15], globoid cell leukodystrophy [16], stroke [17], and Huntington's disease [18], to name just a few. It has truly been an exciting year, as we watch the stem cell field explode.…”