Continuing Challenges in Advancing Preclinical Science in Skeletal Cell-Based Therapies and Tissue Regeneration

Featherall, Joseph; Robey, Pamela Gehron

doi:10.1002/jbmr.3578

Cited by 7 publications

(3 citation statements)

References 62 publications

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“…The success of cell-based constructs developed for regenerative medicine has been hindered considerably due to a nondependable in vivo biological potency of the implant. This has been associated with a lack of in-depth characterization of the in vitro product and its relation to in vivo potency [ 32 , 33 , 34 , 35 , 36 , 37 , 38 ].…”

Section: Factors That Induce Bone Formationmentioning

confidence: 99%

A Review of Recent Developments in the Molecular Mechanisms of Bone Healing

Rodríguez-Merchán

2021

IJMS

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Between 5 and 10 percent of fractures do not heal, a condition known as nonunion. In clinical practice, stable fracture fixation associated with autologous iliac crest bone graft placement is the gold standard for treatment. However, some recalcitrant nonunions do not resolve satisfactorily with this technique. For these cases, biological alternatives are sought based on the molecular mechanisms of bone healing, whose most recent findings are reviewed in this article. The pro-osteogenic efficacy of morin (a pale yellow crystalline flavonoid pigment found in old fustic and osage orange trees) has recently been reported, and the combined use of bone morphogenetic protein-9 (BMP9) and leptin might improve fracture healing. Inhibition with methyl-piperidino-pyrazole of estrogen receptor alpha signaling delays bone regeneration. Smoking causes a chondrogenic disorder, aberrant activity of the skeleton’s stem and progenitor cells, and an intense initial inflammatory response. Smoking cessation 4 weeks before surgery is therefore highly recommended. The delay in fracture consolidation in diabetic animals is related to BMP6 deficiency (35 kDa). The combination of bioceramics and expanded autologous human mesenchymal stem cells from bone marrow is a new and encouraging alternative for treating recalcitrant nonunions.

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Section: Factors That Induce Bone Formationmentioning

confidence: 99%

A Review of Recent Developments in the Molecular Mechanisms of Bone Healing

Rodríguez-Merchán

2021

IJMS

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“…The success of cell‐based constructs developed for regenerative medicine has been hampered largely due to a nonreliable in vivo biological potency of the implant . This has been associated with a lack of in depth characterization of the in vitro product and its relation to in vivo potency.…”

Section: Discussionmentioning

confidence: 99%

Single-cell characterization and metabolic profiling of in vitro cultured human skeletal progenitors with enhanced in vivo bone forming capacity

Bolander

Herpelinck

Chaklader

et al. 2019

Stem Cells Translational Medicine

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Cell populations and their interplay provide the basis of a cell‐based regenerative construct. Serum‐free preconditioning can overcome the less predictable behavior of serum expanded progenitor cells, but the underlying mechanism and how this is reflected in vivo remains unknown. Herein, the cellular and molecular changes associated with a cellular phenotype shift induced by serum‐free preconditioning of human periosteum‐derived cells were investigated. Following BMP‐2 stimulation, preconditioned cells displayed enhanced in vivo bone forming capacity, associated with an adapted cellular metabolism together with an elevated expression of BMPR2. Single‐cell RNA sequencing confirmed the activation of pathways and transcriptional regulators involved in bone development and fracture healing, providing support for the augmentation of specified skeletal progenitor cell populations. The reported findings illustrate the importance of appropriate in vitro conditions for the in vivo outcome. In addition, BMPR2 represents a promising biomarker for the enrichment of skeletal progenitor cells for in vivo bone regeneration.

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“…By insisting on a histological standard for providing the information that was used in the interpretation of an experimental outcome, this approach will be helpful to the advocates of cell-based skeletal repair and the regulatory agencies that must adjudicate the effectiveness of a preclinical application. 16…”

Section: Introductionmentioning

confidence: 99%

Histological Criteria that Distinguish Human and Mouse Bone Formed Within a Mouse Skeletal Repair Defect

Xin

Jiang

Wang

et al. 2019

J Histochem Cytochem.

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The effectiveness of autologous cell-based skeletal repair continues to be controversial in part because in vitro predictors of in vivo human bone formation by cultured human progenitor cells are not reliable. To assist in the development of in vivo assays of human osteoprogenitor potential, a fluorescence-based histology of nondecalcified mineralized tissue is presented that provides multiple criteria to distinguish human and host osteoblasts, osteocytes, and accumulated bone matrix in a mouse calvarial defect model. These include detection of an ubiquitously expressed red fluorescent protein reporter by the implanted human cells, antibodies specific to human bone sialoprotein and a human nuclear antigen, and expression of a bone/fibroblast restricted green fluorescent protein reporter in the host tissue. Using low passage bone marrow-derived stromal cells, robust human bone matrix formation was obtained. However, a striking feature is the lack of mouse bone marrow investment and osteoclasts within the human bone matrix. This deficiency may account for the accumulation of a disorganized human bone matrix that has not undergone extensive remodeling. These features, which would not be appreciated by traditional decalcified paraffin histology, indicate the human bone matrix is not undergoing active remodeling and thus the full differentiation potential of the implanted human cells within currently used mouse models is not being realized.

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Continuing Challenges in Advancing Preclinical Science in Skeletal Cell-Based Therapies and Tissue Regeneration

Cited by 7 publications

References 62 publications

A Review of Recent Developments in the Molecular Mechanisms of Bone Healing

A Review of Recent Developments in the Molecular Mechanisms of Bone Healing

Single-cell characterization and metabolic profiling of in vitro cultured human skeletal progenitors with enhanced in vivo bone forming capacity

Histological Criteria that Distinguish Human and Mouse Bone Formed Within a Mouse Skeletal Repair Defect

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