Allogenic Adipose Tissue-Derived Mesenchymal Progenitor Cells for the Treatment of Knee Osteoarthritis

It is well established that testosterone negatively regulates fat mass in humans and mice; however, the mechanism by which testosterone exerts these effects is poorly understood. We and others have shown that deletion of the androgen receptor (AR) in male mice results in a phenotype that mimics the three key clinical aspects of hypogonadism in human males; increased fat mass and decreased bone and muscle mass. We now show that replacement of the Ar gene specifically in mesenchymal progenitor cells (PCs) residing in the bone marrow of Global-ARKO mice, in the absence of the AR in all other tissues (PC-AR Gene Replacements), completely attenuates their increased fat accumulation. Inguinal subcutaneous white adipose tissue and intra-abdominal retroperitoneal visceral adipose tissue depots in PC-AR Gene Replacement mice were 50–80% lower than wild-type (WT) and 75–90% lower than Global-ARKO controls at 12 weeks of age. The marked decrease in subcutaneous and visceral fat mass in PC-AR Gene Replacements was associated with an increase in the number of small adipocytes and a healthier metabolic profile compared to WT controls, characterised by normal serum leptin and elevated serum adiponectin levels. Euglycaemic/hyperinsulinaemic clamp studies reveal that the PC-AR Gene Replacement mice have improved whole-body insulin sensitivity with higher glucose infusion rates compared to WT mice and increased glucose uptake into subcutaneous and intra-abdominal fat. In conclusion, these data provide the first evidence for an action of androgens via the AR in mesenchymal bone marrow PCs to negatively regulate fat mass and improve metabolic function.

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Treatment of knee osteoarthritis with intra-articular injection of autologous adipose-derived mesenchymal progenitor cells: a prospective, randomized, double-blind, active-controlled, phase IIb clinical trial

Stem Cell Research & Therapy ◽

10.1186/s13287-019-1248-3 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 24

Author(s):

Liangjing Lu ◽

Chengxiang Dai ◽

Zhongwen Zhang ◽

Hui Du ◽

Suke Li ◽

...

Keyword(s):

Clinical Trial ◽

Knee Osteoarthritis ◽

Progenitor Cells ◽

Mesenchymal Progenitor Cells ◽

Double Blind

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A NEUROGENIC GENE EXPRESSION SIGNATURE SUPPORTS HUMAN THERMOGENIC ADIPOSE TISSUE DEVELOPMENT IN VIVO.

10.1101/2021.12.29.474474 ◽

2021 ◽

Author(s):

Javier Solivan-Rivera ◽

Zinger Yang Loureiro ◽

Tiffany DeSouza ◽

Anand Desai ◽

Qin Yang ◽

...

Keyword(s):

Adipose Tissue ◽

Progenitor Cells ◽

Gene Expression Signature ◽

Metabolic Effects ◽

Mesenchymal Progenitor Cells ◽

Thermogenic Adipocytes ◽

Mouse Adipocytes ◽

Species Specific

Human beige/brite thermogenic adipose tissue exerts beneficial metabolic effects and may be harnessed to improve metabolic health. To uncover mechanisms by which thermogenic adipose tissue is generated and maintained we developed a species-hybrid model in which human mesenchymal progenitor cells are induced in vitro to differentiate into white or thermogenic adipocytes and are then implanted into immuno-compromised mice. Upon implantation, thermogenic adipocytes form a more densely vascularized and innervated adipose tissue compared to non-thermogenic adipocytes. Mouse endothelial and stem/progenitor cells recruited by implanted human thermogenic adipocytes are also qualitatively different, with differentially expressed genes mapping predominantly to circadian rhythm pathways. We trace the formation of this enhanced neurovascular architecture to higher expression of a distinct set of genes directly associated with neurogenesis (THBS4, TNC, NTRK3 and SPARCL1), and to lower expression of genes associated with neurotransmitter degradation (MAOA, ACHE) by adipocytes in the developed tissue. Further analysis reveals that MAOA is abundant in human adipocytes but absent in mouse adipocytes, revealing species-specific mechanisms of neurotransmitter tone regulation. In summary, our work discovers specific neurogenic genes associated with development and maintenance of human thermogenic adipose tissue, reveals species-specific mechanisms of control of neurotransmitter tone, and suggests that targeting adipocyte MAOA may be a strategy for enhancing thermogenic adipose tissue activity in humans.

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Generation of functional human adipose tissue in mice from primed progenitor cells

10.1101/267427 ◽

2018 ◽

Cited By ~ 1

Author(s):

Raziel Rojas-Rodriguez ◽

Jorge Lujan-Hernandez ◽

So Yun Min ◽

Tiffany DeSouza ◽

Patrick Teebagy ◽

...

Keyword(s):

Adipose Tissue ◽

Progenitor Cells ◽

Adipogenic Differentiation ◽

Human Adipose Tissue ◽

Cyst Formation ◽

Mesenchymal Progenitor Cells ◽

Genes Encoding ◽

Immunocompromised Mice

AbstarctAdipose tissue is used extensively in reconstructive and regenerative therapies, but transplanted fat often undergoes inflammation and cell death, requiring further revision surgery. We report that functional human adipose tissue can be generated from mesenchymal progenitor cells in-vivo, providing an alternative approach to its therapeutic use. We leveraged previous findings that progenitor cells within the vasculature of human adipose tissue robustly proliferate in 3-dimensional culture under proangiogenic conditions. Implantation of these progenitor cells into immunocompromised mice results in differentiation towards non-adipocyte fates, incapable of generating a distinct tissue structure. However, priming of these progenitor cells in-vitro towards adipogenic differentiation results in formation of functional adipose tissue in-vivo. Mechanistically, priming induces the expression of genes encoding specific extracellular matrix and remodeling proteins, and induces extensive vascularization by host blood vessels. In comparison, grafts from adipose tissue obtained by liposuction undergo poor vascularization, adipocyte death, cyst formation, calcification and inefficient adiponectin secretion. Thus, primed mesenchymal adipose tissue progenitors reveal mechanisms of human adipose tissue development, and have potential to improve outcomes in reconstructive and regenerative medicine.

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Gnas Inactivation Alters Subcutaneous Tissues in Progression to Heterotopic Ossification

Frontiers in Genetics ◽

10.3389/fgene.2021.633206 ◽

2021 ◽

Vol 12 ◽

Author(s):

Niambi Brewer ◽

John T. Fong ◽

Deyu Zhang ◽

Girish Ramaswamy ◽

Eileen M. Shore

Keyword(s):

Adipose Tissue ◽

Heterotopic Ossification ◽

Progenitor Cells ◽

Soft Tissues ◽

Control Cell ◽

Heterotopic Bone ◽

Mesenchymal Progenitor Cells ◽

Tissue Microenvironment ◽

Subcutaneous Tissues ◽

Mutant Cells

Heterotopic ossification (HO), the formation of bone outside of the skeleton, occurs in response to severe trauma and in rare genetic diseases such as progressive osseous heteroplasia (POH). In POH, which is caused by inactivation of GNAS, a gene that encodes the alpha stimulatory subunit of G proteins (Gsα), HO typically initiates within subcutaneous soft tissues before progressing to deeper connective tissues. To mimic POH, we used conditional Gnas-null mice which form HO in subcutaneous tissues upon Gnas inactivation. In response to Gnas inactivation, we determined that prior to detection of heterotopic bone, dermal adipose tissue changed dramatically, with progressively decreased adipose tissue volume and increased density of extracellular matrix over time. Upon depletion of the adipose tissue, heterotopic bone progressively formed in those locations. To investigate the potential relevance of the tissue microenvironment for HO formation, we implanted Gnas-null or control mesenchymal progenitor cells into Gnas-null or control host subcutaneous tissues. We found that mutant cells in a Gnas-null tissue environment induced a robust HO response while little/no HO was detected in control hosts. Additionally, a Gnas-null tissue environment appeared to support the recruitment of control cells to heterotopic bone, although control cell implants were associated with less HO formation compared to mutant cells. Our data support that Gnas inactivation alters the tissue microenvironment to influence mutant and wild-type progenitor cells to contribute to HO formation.

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Isolation and Characterization of Mesenchymal Progenitor Cells From Human Orbital Adipose Tissue

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.14-14441 ◽

2014 ◽

Vol 55 (8) ◽

pp. 4842 ◽

Cited By ~ 13

Author(s):

Szu-Yu Chen ◽

Megha Mahabole ◽

Elan Horesh ◽

Sara Wester ◽

Jeffrey L. Goldberg ◽

...

Keyword(s):

Adipose Tissue ◽

Progenitor Cells ◽

Mesenchymal Progenitor Cells ◽

Isolation And Characterization

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Intra-articular injections of allogeneic human adipose-derived mesenchymal progenitor cells in patients with symptomatic bilateral knee osteoarthritis: a Phase I pilot study

Regenerative Medicine ◽

10.2217/rme-2019-0106 ◽

2020 ◽

Vol 15 (5) ◽

pp. 1625-1636 ◽

Cited By ~ 1

Author(s):

Liangjing Lu ◽

Chengxiang Dai ◽

Hui Du ◽

Suke Li ◽

Ping Ye ◽

...

Keyword(s):

Adverse Events ◽

Knee Osteoarthritis ◽

Phase I ◽

Progenitor Cells ◽

Low Dose ◽

Short Form ◽

High Dose ◽

Mesenchymal Progenitor Cells ◽

End Points ◽

Bilateral Knee

Aim: This study investigated the safety and clinical outcomes of expanded allogeneic human adipose-derived mesenchymal progenitor cells injected into patients with symptomatic, bilateral knee osteoarthritis. Design: In this single-site, randomized, double-blind, dose-ranging, Phase I study, patients were randomized to three treatment groups (low dose, 1 × 107 cells; medium dose, 2 × 107 cells; high dose, 5 × 107 cells). All patients received two bilateral intra-articular injections: week 0 (baseline) and week 3. The primary end point was adverse events within 48 weeks. Secondary end points were measured with Western Ontario and McMaster Universities Osteoarthritis index, visual analog scale, short form-36 at weeks 12, 24 and 48. Quantitative MRI measurements of cartilage volume were compared from baseline and week 48. Results: A total of 22 subjects were enrolled of which 19 (86%) completed the study. Adverse events were transient, including mild to moderate pain and swelling of injection site. Improvements from baseline were measured in the secondary end points. MRI assessments showed slight improvements in the low-dose group. Conclusion: Safety and improvements in pain and function after intra-articular injections of allogeneic human adipose-derived mesenchymal progenitor cells into arthritic patients was demonstrated.

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Multi-compositional MRI evaluation of repair cartilage in knee osteoarthritis with treatment of allogeneic human adipose-derived mesenchymal progenitor cells

Stem Cell Research & Therapy ◽

10.1186/s13287-019-1406-7 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 5

Author(s):

Xinxin Zhao ◽

Jingjing Ruan ◽

Hui Tang ◽

Jia Li ◽

Yingxuan Shi ◽

...

Keyword(s):

Knee Osteoarthritis ◽

Progenitor Cells ◽

Structural Changes ◽

High Dose ◽

Mesenchymal Progenitor Cells ◽

Clinical Evaluations ◽

Sf 36 ◽

Mri Sequences ◽

Magnetic Resonance Imaging Mri ◽

New Treatment

Abstract Background We used multimodal compositional magnetic resonance imaging (MRI) techniques, combined with clinical outcomes, to differentiate the alternations of composition in repair cartilage with allogeneic human adipose-derived mesenchymal progenitor cells (haMPCs) in knee osteoarthritis (KOA) patients. Methods Eighteen patients participated a phase I/IIa clinical trial. All patients were divided randomly into three groups with intra-articular injections of haMPCs: the low-dose (1.0 × 107 cells), mid-dose (2.0 × 107), and high-dose (5.0 × 107) groups with six patients each. Compositional MRI examinations and clinical evaluations were performed at different time points. Results Significant differences were observed in quantitative T1rho, T2, T2star, R2star, and ADC measurements in patients of three dose groups, suggesting a possible compositional changes of cartilage with the treatment of allogeneic haMPCs. Also significant reduction in WOMAC and SF-36 scores showed the symptoms might be alleviated to some extent with this new treatment. As regards sensibilities of multi-parametric mappings to detect compositional or structural changes of cartilage, T1rho mapping was most sensitive to differentiate difference between three dose groups. Conclusions These results showed that multi-compositional MRI sequences might be an effective tool to evaluate the promotion of the repair of cartilage with allogeneic haMPCs by providing information of compositional alterations of cartilage. Trial registration Clinicaltrials, NCT02641860. Registered 3 December 2015.

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