Chondrocyte Progenitors – A New and Effective Cell Therapy for Cartilage Regeneration?

Review of “Human Cartilage-Derived Progenitor Cells from Committed Chondrocytes for Efficient Cartilage Repair and Regeneration” from Stem Cells Translational Medicine by Stuart P. Atkinson

As articular cartilage holds no intrinsic self-reparative potential, injury can often lead to degenerative joint diseases. Treatments include transplantation of autologous chondrocytes (cartilage cells) [1, 2], although better and more efficient cell-based treatments could significantly increase regeneration. Previous studies have described cartilage stem/progenitor cells (CSPCs) before (see original text for extensive references) and they could represent a potentially exciting therapeutic option if we understood more about their basic biology and differentiation capacity.

Researchers from the laboratories of Hong Wei Ouyang (Zhejiang University, Hangzhou, China) and Rocky S. Tuan (University of Pittsburgh, USA) noted that some differentiated cell types could revert back to a stem cell-like fate [3, 4], so does this work for chondrocytes? Their new study in Stem Cells Translational Medicine demonstrates the derivation of chondrocyte-derived progenitor cells (CDPCs) from terminally differentiated human articular chondrocytes and their in vitro and in vivo cartilage repair capacity [5].

The study began when the researchers noted that chondrocytes isolated from adult human articular cartilage took on a stem cell-like fate after in vitro culture, including the upregulation of CD146, an early-stage MSC marker, and the downregulation of collagen type II (COL2), a mature chondrocyte marker. The application of 2D monolayer low-glucose low-cell-density culture conditions, designed to promote and nurture stem-cell growth, aided the emergence, maintenance, and expansion of CD146-positive cells which the authors named chondrocyte-derived progenitor cells (CDPCs). Further in-depth analysis demonstrated that CDPCs and self-renewal capabilities and displayed an MSC-like phenotype with an increased chondrogenic potential.

But can these cells go on to produce hyaline-like cartilage in vitro and, more importantly, in vivo? Thankfully, CDPCs cultured at high-density in 3D conditions in the presence of chondrogenic growth factors mediated the efficient formation of cartilage at 9 weeks. Furthermore, culture of CDPCs within hyaline cartilage-derived acellular matrix (AM) further enhanced cartilage formation suggesting that exposure to the cartilage environment enhanced CDPC chondrogenic potential without the need for externally added factors.

In vivo analysis first assessed subcutaneous injection of CDPCs in the backs of immunodeficient mice, which led to the formation of hyaline cartilage-like tissues by 4 weeks, and through a pilot clinical study. Encouragingly, transplantation into cartilage defects in human patients significantly improved clinical scores, and patients presented with repaired defects, no postoperative complications, signs of chondrocyte-like cells and hyaline cartilage-like structure and matrix (See figure), and reduced knee pain and swelling in all patients.

The description and functional analysis of CDPCs should help the field take a large, bracing, pain-free step towards stem cell-based regenerative therapies for degenerative joint diseases. Furthermore, this provides further evidence that multiple cell types may be able to revert back to a stem cell-like state, and the discovery of the controlling molecular cues may provide a means to modulate cell fate and promote repair in vivo without the need for cell transplantation.

References

1. Brittberg M, Lindahl A, Nilsson A, et al. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med 1994;331:889-895.
2. Jiang YZ, Zhang SF, Qi YY, et al. Cell transplantation for articular cartilage defects: principles of past, present, and future practice. Cell Transplant 2011;20:593-607.
3. Stange DE, Koo BK, Huch M, et al. Differentiated Troy+ chief cells act as reserve stem cells to generate all lineages of the stomach epithelium. Cell 2013;155:357-368.
4. Rompolas P, Mesa KR, and Greco V Spatial organization within a niche as a determinant of stem-cell fate. Nature 2013;502:513-518.
5. Jiang Y, Cai Y, Zhang W, et al. Human Cartilage-Derived Progenitor Cells From Committed Chondrocytes for Efficient Cartilage Repair and Regeneration. Stem Cells Transl Med 2016;5:733-744.