Cell sources proposed for nucleus pulposus regeneration

Abstract

Lower back pain (LBP) occurs in 80% of adults in their lifetime; resulting in LBP being one of the biggest causes of disability worldwide. Chronic LBP has been linked to the degeneration of the intervertebral disc (IVD). The current treatments for chronic back pain only provide alleviation of symptoms through pain relief, tissue removal, or spinal fusion; none of which target regenerating the degenerate IVD. As nucleus pulposus (NP) degeneration is thought to represent a key initiation site of IVD degeneration, cell therapy that specifically targets the restoration of the NP has been reviewed here. A literature search to quantitatively assess all cell types used in NP regeneration was undertaken. With key cell sources: NP cells; annulus fibrosus cells; notochordal cells; chondrocytes; bone marrow mesenchymal stromal cells; adipose-derived stromal cells; and induced pluripotent stem cells extensively analyzed for their regenerative potential of the NP. This review highlights: accessibility; expansion capability in vitro; cell survival in an IVD environment; regenerative potential; and safety for these key potential cell sources. In conclusion, while several potential cell sources have been proposed, iPSC may provide the most promising regenerative potential.

Keywords: biologic therapies; regenerative medicine; stem cell; tissue engineering.

FIGURE 1

Cell sources and linages involved in cellular therapy in regenerating the intervertebral disc. (A) Schematic illustration depicting key stages of intervertebral disc development, highlighting the mesodermal origin of the notochord and sclerotome that evolve into the nucleus pulposus, annulus fibrosus and vertebral bodies. Red arrows show the potential cell sources. (B) An illustration of the mesenchymal stem cell and notochordal cell differentiation lineages (black arrows). Under appropriate culture conditions transdifferentiation can be induced to develop different cell types (black dash arrows), which can interlink different cell lines

FIGURE 2

Publication intensity for cellular therapy for NP regeneration. The number of studies investigating potential cellular therapy to regenerate the NP extracted from the literature review search expanding over 26 years (from January 1994 to December 2020)

FIGURE 3

Cell sources proposed for NP regeneration: Studies investigating potential cellular therapy to regenerate the NP expanding over 26 years (from January 1994 to December 2020) were classified according to cell source proposed: the number (A), percentage (B) of cell type and the percentage of cell type relative to the year (C) which used the following cell types: Adipose derived mesenchymal stem cells (ADMSC), annulus fibrosus (AF) cells, bone marrow derived mesenchymal stem cells (BMSC), chondrocytes (subgroups include: endplate chondrocytes, hyaline chondrocytes, articular chondrocytes, nasal chondrocytes, and auricular chondrocytes), fibroblast cells, gynecological cells (subgroups include: menstrual blood derived stem cells, and human amniotic cells), hematopoietic stem cells, human embryonic stem cells (hESC), human umbilical cord stem cells (hUSC; including placenta derived mesenchymal stem cells), induced pluripotent stem cells (iPSC), muscle derived stem cells, notochordal cells (NC), nucleus pulposus cells (NPC), olfactory stem cells, and synovial derived mesenchymal stem cells. (B) From the literature extracted: 40% used BMSC; 26% used NPC; 12% ADMSC; 6% used chondrocytes; 3% used iPSC; 3% used hUSC; 3% used NC cells; 2% used AF cells; 2% used fibroblasts; <1% used hESC; <1% used synovial MSC; <1% used gynecological cells; <1% used olfactory SC; <1% used muscle SC; <1% hematopoietic SC

FIGURE 4

Study type utilized to investigate cellular regeneration of the NP. Studies investigating potential cellular therapy to regenerate the NP expanding over 26 years (from January 1994 to December 2020) were classified according to the type of study performed; the number (A), percentage (B) of study type and the percentage of study type relative to the year (C) from the literature search that used the following model systems: in vitro (including 2D and 3D culture), tissue explants, organ culture, in vivo (subcutaneous or injected into a healthy or degenerate intervertebral disc), canine clinical trials and human clinical trials

FIGURE 5

Animal model utilized for investigation of cell therapies for NP regeneration. In vivo studies (including human clinical trials, canine clinical trials, and in vivo study types) investigating potential cellular therapy to regenerate the NP expanding over 26 years (from January 1994 to December 2020) were classified according to the animal model utilized; the number (A), percentage of animal model used (B) and the percentage of animal model used relative to the year (C) from the literature search that used the following living animal model system: human, monkey, dog, cow, pig, sheep, goat, rabbit, rat, and mouse