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Enhancing ESC-based Bone Therapeutics with Fibrinogen

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Review of “Fibrinogen Induces RUNX2 Activity and Osteogenic Development from Human Pluripotent Stem Cells” from Stem Cells by Stuart P. Atkinson

The differentiation of pluripotent stem cells (PSCs) into osteoblast bone-forming cells has the potential to be an effective therapeutic tool for diseased or damaged bone. However, current differentiation strategies are ill defined and utilize animal products that limit their clinical translation.

Now, researchers from the laboratory of Dan S. Kaufman (University of California- San Diego, USA) have applied a RUNX2 reporter human embryonic stem cell (hESC) line [1] to characterize the specific conditions that mediate osteogenesis. RUNX2 (or Runt-related transcription factor 2) is a critical and early regulator of osteogenic development [2], and using this system, they have now identified a novel fibrinogen-SMAD1/5/8-RUNX2 signaling axis which promotes osteogenic development [3]. Does this new Stem Cells article have the potential to revolutionize ESC-based bone therapeutics?

First assessments of osteogenic differentiation of hESCs highlighted the use of collagen type I as a superior growth matrix when applied alongside osteogenic media supplemented with 10% FBS. The authors then applied defined serum-free conditions using known osteogenic enhancers (BMP2, FGF9, rapamycin, and Wnt3a) to promote osteogenic differentiation (as observed by an increase in osteogenic markers such as RUNX2, OSTERIX, and DLX5).

Further analysis of serum-components with the ability to boost osteogenesis then demonstrated the importance of fibrinogen. The authors established that this glycoprotein bound to the α9β1 heterodimer integrin receptor on differentiating hESCs, activated the SMAD 1/5/8 pathway, and by this means, boosted the expression of the all-important expression of RUNX2. Importantly, hESCs differentiated using fibrinogen expressed mature osteogenic markers (OSTEOCALCIN, RUNX2, and OSTERIX) and had the ability to produce calcium (Von Kossa staining).

The group also extended these findings from hESCs to induced pluripotent stem cells (iPSCs) derived from human umbilical cord blood; again demonstrating the expression of osteogenic markers and the production of calcium (See Figure).

In this study, the authors demonstrate the utility of their hESC-RUNX2 reporter system through the definition of a novel fibrinogen-α9β1-SMAD1/5/8-RUNX2 signaling axis as in important regulator of osteogenic differentiation. This is an important step towards the clinical application of ESC-based bone therapeutics, as studies such as this will lead to the construction of serum-free and xeno-free differentiation strategies [4]. However, we must first assess the in vivo efficacy of cells differentiated in this manner to repair bone fractures in a suitable model animal.

References

  1. Zou L, Kidwai FK, Kopher RA, et al. Use of RUNX2 expression to identify osteogenic progenitor cells derived from human embryonic stem cells. Stem Cell Reports 2015;4:190-198.
  2. Komori T Regulation of osteoblast differentiation by Runx2. Adv Exp Med Biol 2010;658:43-49.
  3. Kidwai F, Edwards J, Zou L, et al. Fibrinogen Induces RUNX2 Activity and Osteogenic Development from Human Pluripotent Stem Cells. STEM CELLS 2016;34:2079-2089.
  4. Kimbrel EA and Lanza R Current status of pluripotent stem cells: moving the first therapies to the clinic. Nat Rev Drug Discov 2015;14:681-692.