Lysosomal protein surface expression discriminates fat- from bone-forming human mesenchymal precursor cells

Abstract

Tissue resident mesenchymal stem/stromal cells (MSCs) occupy perivascular spaces. Profiling human adipose perivascular mesenchyme with antibody arrays identified 16 novel surface antigens, including endolysosomal protein CD107a. Surface CD107a expression segregates MSCs into functionally distinct subsets. In culture, CD107alow cells demonstrate high colony formation, osteoprogenitor cell frequency, and osteogenic potential. Conversely, CD107ahigh cells include almost exclusively adipocyte progenitor cells. Accordingly, human CD107alow cells drove dramatic bone formation after intramuscular transplantation in mice, and induced spine fusion in rats, whereas CD107ahigh cells did not. CD107a protein trafficking to the cell surface is associated with exocytosis during early adipogenic differentiation. RNA sequencing also suggested that CD107alow cells are precursors of CD107ahigh cells. These results document the molecular and functional diversity of perivascular regenerative cells, and show that relocation to cell surface of a lysosomal protein marks the transition from osteo- to adipogenic potential in native human MSCs, a population of substantial therapeutic interest.

Bone-Forming Perivascular Cells: Cellular Heterogeneity and Use for Tissue Repair

“…Our group recently identified surface CD107a as a marker to segregate functionally relevant cells within the human adventitial cell niche. 33 CD107a immunoreactivity is found most frequently within the outermost layers of blood vessels, and more common in the outer tunica adventitia. FACS-derived CD107a low and CD107a high stromal cells from human white adipose tissue have opposite differentiation potentials.…”

“…27,28 The osteoblastic potential of adventitial cells has been summarized in several recent reviews. 30,31 Perivascular adventitial cells participate directly in bone formation and repair 32,33 as well as indirectly induce bone repair via interaction with native skeletal cells. 34,35 Implanted perivascular cells regenerate bone indirectly via pleiotropic mechanisms, including for example release of extracellular vesicles (EV) 34 as well as nonvesicular paracrine effectors, such as bone morphogenetic proteins.…”

“…We have identified cell subsets in the human adventitia expressing CD10 or CD107a, and distinct differentiation potentials. 33,48 Transcriptomic analysis of human adventitial cells also revealed that high aldehyde dehydrogenase (ALDH) activity marks stem cell-like cells. 29 In this section, we will discuss in detail these novel markers of the human adventitia (Table 1).…”

“…This suggests that Gli1 has similar functions in human and mouse arteries, making it a possible therapeutic target in vascular calcification. We have identified cell subsets in the human adventitia expressing CD10 or CD107a, and distinct differentiation potentials 33,48 . Transcriptomic analysis of human adventitial cells also revealed that high aldehyde dehydrogenase (ALDH) activity marks stem cell‐like cells 29 .…”

“…While CD107a is ubiquitously expressed intracellularly, only a fraction of mammalian cells display detectable surface CD107a. Our group recently identified surface CD107a as a marker to segregate functionally relevant cells within the human adventitial cell niche 33 . CD107a immunoreactivity is found most frequently within the outermost layers of blood vessels, and more common in the outer tunica adventitia .…”