Depletion of Myo/Nog Cells in the Lens Mitigates Posterior Capsule Opacification in Rabbits

Abstract

PURPOSE. Posterior capsule opacification (PCO) is a vision-impairing disease that occurs in some adults and most children after cataract surgery. Contractile myofibroblasts contribute to PCO by producing wrinkles in the lens capsule that scatter light. Myofibroblasts in the lens originate from Myo/Nog cells named for their expression of the MyoD transcription factor and bone morphogenetic protein inhibitor noggin. In this study we tested the effects of depleting Myo/Nog cells on development of PCO. METHODS. Myo/Nog cells were eliminated by injecting the G8 antibody conjugated to 3DNA nanocarriers for the cytotoxin doxorubicin (G8:3DNA:Dox) during cataract surgery in rabbits. The severity of PCO was scored by slit lamp analysis, gross and histologic observation, and immunofluorescence localization of a-smooth muscle actin. RESULTS. G8:3DNA:Dox specifically induced cell death in Myo/Nog cells in the lens. None of the lenses administered G8:3DNA containing 9 to 36 lM doxorubicin developed greater than trace levels of central PCO and few myofibroblasts were present on the capsule. Less than 9% of these lenses exhibited greater than mild levels of peripheral PCO. Doxorubucin itself reduced PCO; however, myofibroblasts and wrinkles were abundant in the lens, and off-target effects were observed in the ciliary processes and cornea. CONCLUSIONS. Myo/Nog cells are the primary source of myofibroblasts in the lens after cataract surgery. Targeted depletion of Myo/Nog cells has potential for preventing PCO and preserving vision.

Myo/Nog cells are nonprofessional phagocytes

“…Double labeling with the G8 and Iba1 mAbs also was performed to examine the relationship between Myo/Nog cells and macrophages in the anterior cavity of the eye (Fig 5). G8+ cells were present throughout the anterior cavity (Fig 5E-5J), as observed previously [13,15,16]. No Iba1+ cells were present in human lens explant cultures ( Fig 5E).…”

“…New Zealand white female rabbits weighing 2.8 to 3.2 kg underwent cataract surgery as described previously [16]. Anesthesia was obtained with an intramuscular injection of ketamine hydrochloride (50 mg/kg) and xylazine (7 mg/kg).…”

“…Myo/Nog cells are attracted to dying cells in the blastocyst, rabbit lens and murine retina [7,10,16]. They also home to wounds in anterior human lens tissue removed during cataract surgery [13,14].…”

“…The dynamic behavior of Myo/Nog cells also has been observed in the lens. Upon injury to the lens epithelium, they migrate to the wound and differentiate into myofibroblasts that synthesize alpha smooth muscle actin (α-SMA) and striated muscle specific proteins [12][13][14][15][16]. Eliminating Myo/Nog cells in explant cultures of human lens tissue with either the targeting G8 monoclonal antibody (mAb) and complement or a drug consisting of the G8 mAb conjugated to 3DNA nanocarriers for doxorubicin prevents the emergence of myofibroblasts [14].…”

“…Eliminating Myo/Nog cells in explant cultures of human lens tissue with either the targeting G8 monoclonal antibody (mAb) and complement or a drug consisting of the G8 mAb conjugated to 3DNA nanocarriers for doxorubicin prevents the emergence of myofibroblasts [14]. Injection of this drug into the rabbit lens during cataract surgery significantly reduces myofibroblasts and mitigates a vision impairing, fibrotic disease called posterior capsule opacification [16].…”