Bone regeneration strategies based on organelle homeostasis of mesenchymal stem cells

Abstract

The organelle modulation has emerged as a crucial contributor to the organismal homeostasis. The mesenchymal stem cells (MSCs), with their putative functions in maintaining the regeneration ability of adult tissues, have been identified as a major driver to underlie skeletal health. Bone is a structural and endocrine organ, in which the organelle regulation on mesenchymal stem cells (MSCs) function has most been discovered recently. Furthermore, potential treatments to control bone regeneration are developing using organelle-targeted techniques based on manipulating MSCs osteogenesis. In this review, we summarize the most current understanding of organelle regulation on MSCs in bone homeostasis, and to outline mechanistic insights as well as organelle-targeted approaches for accelerated bone regeneration.

Keywords: mesenchymal stem cells; organelle regulation; osteogenesis; subcellular homeostasis; target strategies.

Figure 1

Personalized strategies for remodeling mitochondrial homeostasis. The regulation of mitochondrial function that triggers osteogenic differentiation of stem cells includes scavenging excessive ROS (A), metabolic modulation (B), and mitochondrial quality control (C). NAC, N-acetylcysteine; α-LA, alpha-lipoic acid; SOD, superoxide dismutase; CAT, catalase; GSH, glutathione; MnSOD, manganese superoxide dismutase; Ce, cerium; Sr, strontium; NAD⁺, Nicotinamide adenine dinucleotide; α-KG, alpha-ketoglutarate; SAM, S-adenosylmethionine; acetyl CoA, acetyl coenzyme A; Mfn, Mitochondrial fusion protein; HCM, high molecular weight polyacrylic acid (HPAA)-crosslinked collagen membrane.

Figure 2

Design strategies towards to ER stress. Protein misfolding or unfolding can cause disorders in ER homeostasis, leading to ER stress. If ER stress is not resolved in time, unfolded or misfolded proteins accumulate in the ER, and the UPR triggers a cascade through IRE1α, ATF6, and PERK signaling pathways. At the same time, fluctuations in ER and mitochondrial Ca²⁺ homeostasis can trigger interactions between organelles. The establishment of therapeutic strategies for ER stress has become an indispensable part of regulating ER homeostasis to promote osteogenic differentiation. UPR, unfolded protein response; TMCO1, transmembrane and helix-coil structural domain 1, 4-PBA: 4-phenylbutiric acid.

Figure 3

From sensing microenvironmental signals to gene modulation of nuclear-targeted guidelines. Physicochemical cues including matrix stiffness (A), topology (B), pore size (C), and nuclear gene modifications (D) manipulate the osteogenic differentiation tendency of MSCs. PCL, polycaprolactone; PLA, polylactic acid; PDMS, polydimethylsiloxane; PEG, poly (ethylene glycol); INM, inner nuclear membrane; ONM, outer nuclear membrane; NPCs, nuclear pore complexes.