Hypoxic culture conditions induce increased metabolic rate and collagen gene expression in ACL-derived cells

Tomasz J. Kowalski, Natalie L. Leong, Ayelet Dar, Ling Wu, Nima Kabir, Adam Z. Khan, Claire D. Eliasberg, Andrew Pedron, Ashant Karayan, Siyoung Lee, Theodor Di Pauli Von Treuheim, Jin Jiacheng, Ben M. Wu, Denis Evseenko, David R. McAllister, Frank A. Petrigliano

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


There has been substantial effort directed toward the application of bone marrow and adipose-derived mesenchymal stromal cells (MSCs) in the regeneration of musculoskeletal tissue. Recently, resident tissue-specific stem cells have been described in a variety of mesenchymal structures including ligament, tendon, muscle, cartilage, and bone. In the current study, we systematically characterize three novel anterior cruciate ligament (ACL)-derived cell populations with the potential for ligament regeneration: ligament-forming fibroblasts (LFF: CD146neg, CD34negCD44pos, CD31neg, CD45neg), ligament perivascular cells (LPC: CD146posCD34negCD44pos, CD31neg, CD45neg) and ligament interstitial cells (LIC: CD34posCD146neg, CD44pos, CD31neg, CD45neg) - and describe their proliferative and differentiation potential, collagen gene expression and metabolism in both normoxic and hypoxic environments, and their trophic potential in vitro. All three groups of cells (LIC, LPC, and LFF) isolated from adult human ACL exhibited progenitor cell characteristics with regard to proliferation and differentiation potential in vitro. Culture in low oxygen tension enhanced the collagen I and III gene expression in LICs (by 2.8- and 3.3-fold, respectively) and LFFs (by 3- and 3.5-fold, respectively) and increased oxygen consumption rate and extracellular acidification rate in LICs (by 4- and 3.5-fold, respectively), LFFs (by 5.5- and 3-fold, respectively), LPCs (by 10- and 4.5-fold, respectively) as compared to normal oxygen concentration. In summary, this study demonstrates for the first time the presence of three novel progenitor cell populations in the adult ACL that demonstrate robust proliferative and matrix synthetic capacity; these cells may play a role in local ligament regeneration, and consequently represent a potential cell source for ligament engineering applications.

Original languageEnglish
Pages (from-to)985-994
Number of pages10
JournalJournal of Orthopaedic Research
Issue number6
StatePublished - 1 Jun 2016
Externally publishedYes


  • ACL
  • stem cell


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