Human Pluripotent Stem Cells: Advances in Chondrogenic Differentiation and Articular Cartilage Regeneration
Human Pluripotent Stem Cells: Advances in Chondrogenic Differentiation and Articular Cartilage Regeneration
Rosa M. Guzzo 0
Michael B. O'Sullivan 0
0 Department of Orthopaedic Surgery, UConn Health Center , 263 Farmington Avenue, Farmington, CT , USA
Articular chondral lesions are major risk factors for the development of osteoarthritis (OA). Multiple adult cellbased approaches have been attempted to restore hyaline cartilage and prevent progressive degeneration; however, the formation of permanent cartilage has not yet been achieved. A scalable source of cartilage progenitors may have far-reaching potential to advance joint cartilage therapy as well as disease modeling and would be expected to facilitate the discovery of novel therapeutics to stimulate cartilage regeneration or prevent degeneration. Because of their unlimited proliferative capacity and pluripotency, human pluripotent stem cells have become an attractive therapeutic option as a source for consistently uniform cells with high chondrogenic capacity. This review focuses on the recent progress using developmentbased paradigms to control the differentiation of human pluripotent stem cells to an articular chondrocyte fate. We highlight recent findings that demonstrate the promise for using pluripotent stem cell-based replacement for hyaline cartilage repair.
Articular cartilage repair; Embryonic stem cells; Induced pluripotent stem cells; Mesenchymal stem cells; Osteoarthritis; Regeneration
Introduction
Osteoarthritis (OA) is a common and debilitating joint disease
for which primary risk factors are traumatic joint injury or
mechanical disruption of joint tissues. There is currently no
cure for OA. Although the true prevalence of articular
chondral lesions in the general public is unknown,
approximately 60 % of patients undergoing knee arthroscopy have
evidence of cartilage lesions [
1, 2
]. The natural history of
articular cartilage lesions is poorly understood, as the means
for evaluating these lesions (MRI, arthroscopy) are not
commonly used for surveillance due to cost implications. A
prevailing notion is that chondral lesions increase in size and
predispose patients to developing OA. Supporting this idea
is evidence that articular cartilage has limited regenerative
capacity, is poorly vascularized, and has a small cell-to-matrix
volume and a very low mitotic rate [3]. Treatment options for
OA patients such as total joint arthroplasty provide excellent
outcomes by ameliorating pain and improving function.
However, many patients sustain cartilage injuries when they
are young and are not good candidates for these procedures as
they would outlive their implant and would require multiple
revision surgeries [
2, 4–6
]. Currently, the prevalence of
patients living in the USA with a total hip or total knee
arthroplasty is estimated to be 7.2 million, which is higher
than the prevalence of stroke (6.8 million) and heart failure
(5.1 million) and approaches that of myocardial infarction (7.6
million) [7]. Thus, OA is an important public health issue, and
there remains an urgent and growing need to develop
regenerative techniques for articular cartilage to treat symptomatic
patients and potentially circumvent the onset of OA among
individuals predisposed to developing OA.
Multiple strategies have been attempted for joint cartilage
surface restoration, with the goal of improving joint function
and delaying or preventing degeneration. However,
regeneration of hyaline cartilage has not been achieved. Introduced by
Brittberg et al. in 1994, implantation of in vitro expanded
autologous human articular chondrocytes (hACs) is a widely
used surgical procedure to treat focal chondral lesions in the
knee joint [
8
]. Autologous chondrocyte implantation (ACI)
involves extraction of a small cartilage biopsy from a
nonload-bearing site within the affected knee joint and in vitro
expansion of the isolated chondrocytes using Bgood
manufacturing practice^ (GMP) laboratory procedures, which
is then followed by implantation of these cells to the defect site
in a second surgical procedure [
8
]. The repair tissue is often
fibrocartilaginous, with little hyaline cartilage restoration [
9,
10
]. Fibrocartilage generally deteriorates over time because of
its inferior structural and mechanical properties, which
increases the likelihood of OA and the need for further surgical
intervention.
Adult mesenchymal stem cells, commonly isolated from
bone marrow, have been extensively examined as an
alternative to either autologous or allogeneic chondrocytes for
regeneration of articular cartilage. These cells offer advantages of
ease of harvest using minimally invasive procedures, low
immunogenicity, high proliferative indices, and an intrinsic
chondrogenic capacity that can be exploited to yield vast
quantities of chondroprogenitors to repair cartilage defects
[
11
]. However, chondrogenic differentiation in bone
marrow-derived MSCs (BMSCs) follows an endochondra (...truncated)